JAC Advance Access originally published online on August 18, 2006
Journal of Antimicrobial Chemotherapy 2006 58(4):830-839; doi:10.1093/jac/dkl275
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Antimicrobial practice |
Antibiotic use among children in British Columbia, Canada
1 University of British Columbia Vancouver, BC, Canada 2 British Columbia Centre for Disease Control Vancouver, BC, Canada 3 Division of Infectious Diseases, Department of Medicine, Vancouver Hospital and Health Sciences Centre Vancouver, BC, Canada
*Corresponding author. Tel: +1-604-660-0386; Fax: +1-604-775-2718; E-mail: fawziah.marra{at}bccdc.ca
Received 27 April 2006; returned 19 May 2006; revised 2 June 2006; accepted 5 June 2006
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Abstract |
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Background: In North America use of second-generation macrolides such as clarithromycin and azithromycin is popular due to favourable dosing and adverse event profiles. However, studies have also shown that use of second-generation macrolides promotes carriage of macrolide-resistant nasopharyngeal and oral streptococci. The present study was undertaken to characterize overall antibiotic use including macrolide antibiotics among children in British Columbia.
Methods: Population-based data from British Columbia were analysed to determine antibiotic prescribing patterns for outpatient prescriptions from 1996 to 2003. Antibiotic prescription rates per 1000 children per year were evaluated by age (0–4, 5–9, 10–14, <15 years old), sex and physician diagnosis.
Results: From 1996 to 2003, the overall BC prescription rate in children <15 years old decreased by one-third from 720 to 488 per 1000 children. The decrease in the rate of antibiotic consumption over time was seen across all age strata; however, the largest decrease (33%) was seen in children between the ages of 0–4 years. From 1996 to 2003, use of penicillins and cephalosporins decreased by 40% and 30%, respectively. This trend of decreasing antibiotic use with ß-lactams was seen in all age groups but the greatest decline was in the age group of 0–4 years (P value <0.05). During this time, macrolide use increased significantly (24%) from 102 to 126 per 1000 children (P value <0.001). This increase was seen in all age groups but again the greatest increase was seen in children of age between 0 and 4 years. Within the macrolides, use of erythromycin decreased by 72% (from 83 to 23 per 1000 children) while clarithromycin use increased by almost 3-fold (18–67 per 1000 children) and azithromycin use increased 81-fold (0.4–35 per 1000 children). In 2003, antibiotics were primarily being used for the treatment of upper respiratory tract infections, acute otitis media and bronchitis.
Conclusions: Overall antibiotic use has declined in children; however, there is increased use of macrolides which may have ramifications on macrolide-resistant streptococci, including Streptococcus pneumoniae and group A streptococci. A large proportion of antibiotic use in children is for upper respiratory tract infections and bronchitis, indications where there is a high likelihood that the aetiology is viral rather than bacterial.
Keywords: paediatrics , antibiotic prescriptions , macrolides
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Introduction |
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In Canada, antibiotics are the fourth mostly commonly prescribed class of agents, after cardiovascular medications, psychotherapeutic drugs and hormones.1 In the 1990s, the number of antibiotics dispensed per year increased steadily and reached a peak of 27.3 million prescriptions in 1997.2 However, campaigns targeting healthcare professionals on decreasing antibiotic use and a greater public awareness on antibiotic misuse has resulted in a 14% decrease in the number of prescriptions dispensed such that in 2004 23.4 million prescriptions of antibiotics were dispensed in Canada.1
Despite the decreasing use of antibiotics within Canada, the prevalence of antimicrobial-resistant organisms, particularly Streptococcus pneumoniae, is increasing and has become a significant threat to public health.3 S. pneumoniae is responsible for a high proportion of community-acquired infections in the paediatric population, including meningitis, otitis media, sinusitis and pneumonia.4–6 Current evidence suggests that the use of certain antibiotics such as extended-spectrum penicillins, cephalosporins and macrolides7,8 has contributed to the increasing development of penicillin-resistant and macrolide-resistant pneumococci.9
Although the data shows a decline in overall prescribing of antibiotics within Canada,1 there are limited data on antibiotic prescribing in children within primary care. Our initial study on antibiotic prescribing rates for the entire population of British Columbia suggested that antibiotic prescribing was decreasing over time; however, the use of second-generation macrolides and fluoroquinolones was increasing.10 We conducted a similar study in children to determine trends across various classes of antibiotics in children less than 15 years of age within British Columbia.
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Methods |
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Antibiotic prescription data
Data were obtained from the PharmaNet (College of Pharmacists) and Medical Services Plan (MSP) databases11 in British Columbia; the reliability and validity of both datasets are high with underreporting and misclassification being minimal. The PharmaNet database contains a record for all ambulatory care prescriptions dispensed to the population of British Columbia. Data within this dataset include the date of dispensing, drug name and dose, duration of treatment, age, sex and geographic location of the pharmacy. Prescriptions included in the database were from the Anatomical Therapeutic Chemical (ATC) categories J01—Antibacterials for Systemic Use.12 The annual rates of antibiotic prescriptions per 1000 children during the years 1996–2003 were reported for all antibiotics for systemic use (J01) and for the six major classes of antibiotics including tetracyclines (J01A), penicillins (J01C), cephalosporins (J01DA), sulphonamides and trimethoprim (J01E), macrolides, lincosamides and streptogramins (J01F), and quinolones (J01M). Within the category of macrolides, we categorized the second-generation macrolides as spiramycin, clarithromycin, azithromycin and telithromycin.
The PharmaNet database was used to determine antibiotic consumption in children over time. Data were obtained for all children less than 15 years of age in primary care and further stratified by age (0–4 years, 5–9 years, 10–14 years) and sex. Data were expressed as the rate of prescriptions per 1000 children rather than daily defined dose to better reflect prescribing activity since the daily defined doses are not accurate for children whose antibiotic dosing is dependent on weight. The population estimates were obtained from Health Data Warehouse and defined as children within that age-sex group. The Medical Services Plan database has patient age, sex, date of visit, physician reimbursement claims (according to International Classification of Diseases, Ninth Revision),13 physician specialty and geographic location of the physician office. For the present study, we used the following diagnostic categories: acute otitis media, bronchitis, upper respiratory tract infection, pneumonia, laryngitis or pharyngitis, sinusitis, lower urinary tract infection and skin/soft tissue infection.
Records from the PharmaNet database were linked with the MSP data by a third party using the patient's personal health number; however, personal identifiers were removed in the final dataset used for analysis. Record linkages were for the years 1996–2003 and each antibiotic prescription was linked to the most recent physician visit during the 5 days preceding dispensing of the prescription. Dispensing of prescriptions which could not be linked to a visit (e.g. refills or phone prescriptions) was excluded from the analysis. The linked database was used to determine for what indications the antibiotics were being prescribed.
Statistical analysis
Trends in prescribing rates and differences between age groups were analysed for statistical significance using generalized linear models. In order to stabilize the variance of the consumption rates that follow a Poisson distribution, square root transformation on the rates were used as the dependent variable in the modelling. All analyses were conducted using SAS statistical software, version 9.1 (SAS Institute, Cary, NC, USA). A P value of <0.05 was considered statistically significant.
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Results |
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Overall antibiotic consumption
The PharmaNet database showed that 3 821 729 prescriptions were dispensed from 1996 to 2003 for children less than 15 years of age. After linking with the MSP database, a total of 3 176 523 records remained; thus, 83% of the prescriptions dispensed were linked to a prior visit to a physician office. The rest of the records were not analysed and would have been prescriptions from physicians by phone, refills or out of town residents. In 1996, the annual rate of antibiotic consumption in children less than 15 years of age was 720 per 1000 children. This decreased by 32% to 488 prescriptions per 1000 children in 2003 (P value <0.001) (Figure 1). The lowest rate of consumption, however, was seen in 2002 with 450 prescriptions per 1000 children.
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The decrease in the rate of antibiotic consumption over time was seen across all age stratifications; however, the largest decrease was seen in children aged between 0 and 4 years (0–4 years: 33%; 5–9 years: 31%, 10–14 years: 25%; all P values <0.05) (Figure 1). In 1996, the prescription rate of antibiotics in children between 0 and 4 years was two times higher than the 10–14 year group. A similar trend was also seen in 2003, with 688 prescriptions per 1000 children being used in the 0–4 year age group compared with 342 prescriptions per 1000 children being used in the 10–14 year age group (i.e. twice as much). When evaluating differences in antibiotic use according to sex, there was no statistically significant difference between males and females, and in both cases antibiotic prescribing rates decreased by 32% from 1996 to 2003.
Class-specific consumption
Table 1 shows the class-specific consumption rates for all children less than 15 years of age but stratified according to the six major ATC classes of antibiotics. For all children less than 15 years of age, the largest decrease in consumption rate was seen with trimethoprim/sulfamethoxazole. In 1996, the use of trimethoprim/sulfamethoxazole for treatment of bacterial infections was 93 prescriptions per 1000 children; this rate decreased by 63% to 34 prescriptions per 1000 children in 2003. The consumption rate of ß-lactams (i.e. penicillins and cephalosporins) also decreased significantly over time. In 1996, the rate of penicillin use was 414 prescriptions per 1000 children but fell by 40% to 249 prescriptions per 1000 children in 2003. Similarly for the cephalosporins, the rate decreased by 30% from 106 per 1000 children in 1996 to 74 per 1000 children in 2003. This trend of decreasing antibiotic use with trimethoprim/sulfamethoxazole and ß-lactams was seen in all age groups but the greatest decline for both antibiotic classes was in the age group of 0–4 years. For trimethoprim/sulfamethoxazole, there was a 65% decrease in use while the ß-lactams decreased by 38% in the 0–4 year age category. In the 5–9 year age group, trimethoprim/sulfamethoxazole consumption decreased by 60% and ß-lactams by 36%. Antibiotic consumption declined by the smallest percentage in the 10–14 year olds with trimethoprim/sulfamethoxazole and ß-lactams decreasing by 56% and 32%, respectively. Ninety-nine per cent of tetracycline use was contributed largely by the 10–14 year old children. The consumption rate of tetracyclines has remained relatively stable over the 7 year study period (3.6 per 1000 children in 1996 to 3.7 per 1000 children in 2003).
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The rate of antibiotic consumption increased for both the macrolide/lincosamide/streptogramin and quinolone antibiotic classes. From 1996 to 2003, macrolide consumption increased by 24% from 102 to 126 prescriptions per 1000 children. This increasing trend seen in the consumption of macrolides was reflected in all three age stratifications but once again the greatest increase was seen in the 0–4 year group (44% increase in the 0–4 years; 19% increase in the 5–9 years; and 12% increase in the 10–14 years). Quinolone consumption also increased over the 7 year study period from 0.59 to 0.84 prescriptions per 1000 children (i.e. 42%); however, the increasing trend for quinolones was only significant for age groups 5–9 (15%) and 10–14 (36%).
Table 1 and Figure 2 show the use of the specific type of penicillins from 1996 to 2003. In British Columbia, extended-spectrum penicillins account for the majority of antibiotic use within the class of penicillins. For example, in 2003, extended-spectrum penicillins (e.g. amoxicillin and ampicillin) accounted for 85% of penicillin prescriptions while the ß-lactamase-sensitive penicillins (e.g. penicillin V) were used 6% of the time and combinations of penicillins (e.g. amoxicillin/clavulanate) account for 5% of all penicillin prescriptions. Figure 3 shows the use of the specific types of macrolides within British Columbia over time. In 1996, erythromycin use accounted for 83 prescriptions per 1000 children. But this has declined significantly, and in 2003 the erythromycin prescription rate was 23 per 1000 children (–72%). In contrast, use of clarithromycin increased by 269% from 18.2 (1996) to 67.0 (2003) prescriptions per 1000 children (P < 0.001). Use of azithromycin has also increased from 0.4 prescriptions per 1000 children to 34.9 prescriptions per 1000 children (an increase of 8056%).
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Antibiotic prescription rates according to specific diagnosis
Children less than 15 years of age. Table 2 shows the change in population-based rates of antibiotic prescribing for each condition over the 7 year study period. From 1996 to 2003, antibiotic prescribing rates decreased significantly for all indications except treatment of pneumonia, which saw an increase in prescribing rates. The largest decrease was seen in the use of antibiotics for the treatment of acute otitis media, which decreased by approximately one-half by 2003. In 1996, use of antibiotics for upper respiratory tract infections was the second most common indication but by 2003 it was the most common reason for antibiotic prescriptions in children less than 15 years of age, particularly acute pharyngitis (41 prescriptions per 1000 children) and tonsillitis (24 prescriptions per 1000 children). Antibiotic prescriptions for treatment of bronchitis also declined by approximately one-third in the 7 year time frame; the majority of this was accounted for by a decrease in prescriptions for acute bronchitis and bronchiolitis (–36%).
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Table 3 shows the trend in antibiotic prescribing rates from 1996 to 2003, according to the diagnostic indications (ICD-9 codes) and age stratifications of 0–4 years, 5–9 years and 10–14 years. All three cohorts of children had a substantial drop in the rate of antibiotic prescribing for acute otitis media, bronchitis and upper respiratory tract infection. The decrease in antibiotic prescribing rates was similar across the three age groups with acute otitis media prescriptions decreasing by 43% in the 0–4 year old children, 48% in the 5–9 year old children and 42% in the 10–14 year old children. Prescriptions for treatment of bronchitis decreased by 34% in the 0–4 and 5–9 year old children and 29% in the 10–14 year old children while prescriptions for treatment of upper respiratory tract infections decreased by
28% in all age groups (30% in the 0–4 year olds; 25% in the 5–9 year olds; 26% in the 10–14 year olds). In contrast, antibiotic prescribing increased in all three age groups for the treatment of pneumonia with the largest increase seen in the 0–4 year olds (39%).
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Children 0–4 years of age. In 2003, prescriptions for the treatment of acute otitis media (185 prescriptions per 1000 children), particularly suppurative and unspecified otitis media (163 prescriptions per 1000 children), accounted for the majority of antibiotic use in the 0–4 year olds (Table 3). In this age group, the class of penicillins followed by the class of macrolides were the most commonly used antibiotics (Table 4). Amoxicillin was used most commonly (107 prescriptions per 1000 children) followed by clarithromycin (18 prescriptions per 1000 children) and azithromycin (16 prescriptions per 1000 children). However the trend from 1996 to 2003 for antibiotic use in the treatment of acute otitis media for children between the ages of 0 and 4 years was a reduction in the use of penicillins by –42% but an increase in the use of macrolides by 146%. In 2003, macrolides were the preferred agents for treatment of bronchitis and pneumonia in the 0–4 year olds. For bronchitis, clarithromycin was the most common agent to be used (17 prescriptions per 1000 children) while azithromycin use was 11 prescriptions per 1000 children. Similarly, for pneumonia, clarithromycin use accounted for six prescriptions per 1000 children and azithromycin use was three prescriptions per 1000 children. Between 1996 and 2003, the use of macrolides for the treatment of bronchitis and pneumonia increased 33% and 233%, respectively, for the 0–4 year olds.
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Children 5–9 years of age and 10–14 years of age. In 2003, the majority of antibiotic use for the 5–9 and 10–14 year olds was for treatment of upper respiratory tract infections (Table 3), particularly for the treatment of acute pharyngitis (5–9 year olds, 44 prescriptions per 1000 children; 10–14 year olds, 40 prescriptions per 1000 children). For this indication, penicillins were the most commonly used antibiotic in both age groups, particularly amoxicillin (5–9 year olds, 67 prescriptions per 1000 children; 10–14 year olds, 50 prescriptions per 1000 children). Macrolide use accounted for
21% of all antibiotic use for this indication in both age groups. Specifically, in the 5–9 year olds, clarithromycin and azithromycin use was 13 and 5 prescriptions per 1000 children, respectively, and in the 10–14 year olds clarithromycin and azithromycin accounted for 10 and 4 prescriptions per 1000 children, respectively. Although the use of penicillins accounts for the majority of antibiotic use in 2003 for the treatment of upper respiratory tract infections, this has declined significantly since 1996 (5–9 year olds, –27%; 10–14 year olds, –30%) while the use of macrolides has remained stable for both age cohorts between 1996 and 2003.
For the 5–9 year olds and 10–14 year olds, the use of macrolides was more common than penicillins in the treatment of bronchitis or pneumonia; here macrolide use accounted for 57% of overall antibiotic use for bronchitis and 75% of overall antibiotic use for pneumonia. Compared with 1996, the use of macrolides for the treatment of pneumonia increased by 133% for the 5–9 year olds and 81% for the 10–14 year olds but for bronchitis has remained stable over the 7 year time frame of the present study.
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Discussion |
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Our population-based study included more than 3 million prescriptions of antibiotics for all children in the province of British Columbia from 1996 to 2003. Our results show that antibiotic use within the community declined by one-third from 1996. This decrease was seen across all age groups of children but the largest drop was seen in children between the ages of 0 and 4 years. Despite this drop seen in the youngest age cohort of our study, antibiotic prescriptions were twice as high in the 0–4 year olds as the 10–14 year olds. Our study also found that the largest decrease in the use of antibiotics occurred with the class of sulfamethoxazole and trimethoprim, which declined by
63% from 1996 to 2003. Similarly, the use of ß-lactams also decreased in the 7 year study period, with all age cohorts seeing an 38% decline in use of penicillins and cephalosporins.
Although our results show a dramatic decline in antibiotic consumption over time, we also see an increase in the use of second-generation macrolide antibiotics in British Columbian children. In British Columbia, the provincial formulary only carries two types of second-generation macrolides—clarithromycin and azithromycin. Overall macrolide consumption increased by 24% between 1996 and 2003 and the majority of this increase was accounted for by use of the second-generation macrolides such as clarithromycin and azithromycin. Within the class of macrolides, clarithromycin use increased 3-fold while azithromycin use increased by 81-fold during the 7 year study period. Most of the increase in the use of macrolides was seen in the 0–4 year olds—children in this age group saw a 44% rise in the use of macrolides from 1996 to 2003 while children between the ages of 5 and 9 years and 10 and 14 years saw a 19% and 12% increase, respectively.
The overall decrease in antibiotic use in children has now been reported by a number of jurisdictions in Europe14–16 and North America.17–19 Like our study, these investigators report a drop of about one-third in overall antibiotic prescriptions, with the greatest drop occurring in the youngest cohort (i.e. 0–4 year olds). Of note, one of these studies was a Canadian study that used the Manitoba population-based database and researchers showed an overall decline in antibiotic use by 28% from 1995 (1201 prescriptions per 1000 children) to 2001 (864 per 1000 children).19 In addition, some of these studies also report a shift from use of the old narrow-spectrum antibiotics to use of more broad-spectrum agents such as the extended-spectrum penicillins (e.g. amoxicillin) and second-generation macrolides such as clarithromycin and azithromycin in the paediatric population.15,18–20
Our study findings corroborate what others have seen around the world.19–21 For example, Stille et al. found a 241% increase in the dispensing of second-generation macrolides for children less than 6 years of age between 1996 and 2000 while the National Ambulatory Medical Care Survey (NAMCS) found a 320% increase in macrolide use in children less than 5 years of age from 1993 to 1999.20,21 The increase in use of the second-generation macrolides seen in our study is slightly higher given that our overall increase over a period of 7 years was 450%. The increase seen with the use of macrolides is concerning since there is new evidence now to suggest that overuse of macrolides not only leads to the development of macrolide-resistant streptococci but also S. pneumoniae and Streptococcus pyogenes that are resistant to both penicillins and macrolides.22,23 This may be particularly true for azithromycin, which has a long elimination half-life and can therefore reside in tissues for a prolonged period of time at subinhibitory concentrations, resulting in an environment that selects for resistant organisms; the same may not be the case for clarithromycin.24
Our study is unique in that it evaluated reasons for prescribing antibiotics at a population level. In 2003, use of antibiotics for the treatment of upper respiratory tract infections accounted for 24% of overall antibiotic use. This is a change from 1996 when the most common indication for prescribing antibiotics was for acute otitis media (26% of overall antibiotic use). This decrease in the use of antibiotics for otitis media is likely due to clinicians using antibiotics judiciously or using the ‘watchful waiting’ approach in the treatment of otitis media. The use of antibiotics for upper respiratory tract infections and bronchitis in children would indicate that more work is required in British Columbia to educate physicians on judicious use of antibiotics and in particular promote the use of penicillins rather than second-generation macrolides. For example, for the treatment of acute otitis media high dose amoxicillin is just as effective as the extended-spectrum macrolides. Most upper respiratory tract infections, including acute pharyngitis and laryngitis, are viral in origin and therefore the use of antibiotics should be minimal for this category.25–27 If the infection is bacterial, then once again the use of macrolides is unnecessary since these infections are mostly due to S. pyogenes, which is presently susceptible to narrow-spectrum penicillins such as penicillin V.25
Our study did not evaluate the reasons for antimicrobial prescribing and overuse; however, other studies have found several reasons for over prescribing including perceived or real pressure from patients and parents of patients to prescribe drugs, inadequate knowledge of the proper indications for some drugs, lack of awareness of prescription guidelines, lack of time to explain to the patient that antimicrobials are not needed, lack of education about resistance patterns in the community, fee-for-service remuneration of physicians and availability of product on the national formulary.28 In order to change prescribing behaviour of clinicians and patient expectations of receiving an antibiotic prescription, multifaceted interventions are required.28 In other words, passive education through conferences or use of written material alone will not change physician or patient behaviour.29 Public health will need to educate all clinicians and the public through multiple means, such as use of written material, pre-printed guidelines, pre-printed prescription pads, written guidelines, reminder methods on treatment guidelines, media campaigns for the public and teaching of healthcare professionals, daycare staff and school children on the need to reduce antibiotic prescribing and when it is necessary to use narrow-spectrum agents.
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Conclusions |
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For the past 5 years, the public health community and infectious diseases physicians have been delivering a unified message to family physicians and the public on decreasing antibiotic use and this has had an impact in British Columbia. However, our study suggests that a new message is needed—to decrease the use of extended-spectrum macrolides and increase the use of ß-lactams when antibiotics are necessary. In addition, we need to continue decreasing the use of antibiotics for the treatment of upper respiratory tract infections and bronchitis.
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Transparency declarations |
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None of the authors on this manuscript has received funds for speaking at symposia organized on behalf of industry nor have they received funds for research from industry. None of the authors holds any stocks in industry.
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Acknowledgements |
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Accepted as a slide presentation at the Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2005. We thank the College of Pharmacists of British Columbia and the BC Ministry of Health for providing the data to the BC Centre for Disease Control. Financial support: the study was funded by a BC Medical Services Foundation (Vancouver Foundation) operating grant.
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References |
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Granizo JJ, Aguilar L, Casal J, et al. (2000) Streptococcus pneumoniae resistance to erythromycin and penicillin in relation to macrolide and ß-lactam consumption in Spain (1979–1997). J Antimicrob Chemother 46:767–73.
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Hogberg L, Oke T, Geli P, et al. (2005) Reduction in outpatient antibiotic sales for pre-school children: interrupted time series analysis of weekly antibiotic sales data in Sweden 1992–2002. J Antimicrob Chemother 56:208–15.
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Otters HB, van der Wouden JC, Schellevis FG, et al. (2004) Trends in prescribing antibiotics for children in Dutch general practice. J Antimicrob Chemother 53:361–6.
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Finkelstein JA, Stille C, Nordin J, et al. (2003) Reduction in antibiotic use among US children, 1996–2000. Pediatrics 112:620–7.
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Linder JA, Bates DW, Lee GM, et al. (2005) Antibiotic treatment of children with sore throat. JAMA 294:2315–22.
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Kozyrskyj AL, Carrie AG, Mazowita GB, et al. (2004) Decrease in antibiotic use among children in the 1990s: not all antibiotics, not all children. CMAJ 171:133–8.
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Stille CJ, Andrade SE, Huang SS, et al. (2004) Increased use of second-generation macrolide antibiotics for children in nine health plans in the United States. Pediatrics 114:1206–11.
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Hyde TB, Gay K, Stephens DS, et al. (2001) Macrolide resistance among invasive Streptococcus pneumoniae isolates. JAMA 286:1857–62.
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Garcia-Rey C, Aguilar L, Baquero F, et al. (2002) Pharmacoepidemiological analysis of provincial differences between consumption of macrolides and rates of erythromycin resistance among Streptococcus pyogenes isolates in Spain. J Clin Microbiol 40:2959–63.
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29
Nash DR, Harman J, Wald ER, et al. (2002) Antibiotic prescribing by primary care physicians for children with upper respiratory tract infections. Arch Pediatr Adolesc Med 156:1114–9.
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