Published online June 1, 2006
PEDIATRICS Vol. 117 No. 6 June 2006, pp. e1104-e1110 (doi:10.1542/peds.2005-2443)
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Antibiotic Treatment of Wheezing in Children With Asthma: What Is the Practice?

Anita L. Kozyrskyj, PhDa,b,c, Matthew E. Dahl, BScb, Wendy J. Ungar, PhDd, Allan B. Becker, MDc and Barbara J. Law, MDc,e

a Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada
b Department of Community Health Sciences, Manitoba Centre for Health Policy, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
c Department of Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba
d Population Health Sciences, The Hospital for Sick Children; Department of Health Policy Management and Evaluation, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
e Department of Medical Microbiology; Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. Antibiotics are not recommended for the treatment of wheezing in children with asthma, but little is known about their use. This study was undertaken to evaluate trends and determinants of antibiotic use in children with wheezing during the fiscal years 1995 through 2001.

METHODS. Using the population-based health care and prescription databases in Manitoba, Canada, this descriptive study examined time trends in antibiotic prescription use for wheezing episodes in a population of children with asthma. The likelihood of receiving an antibiotic prescription according to child and physician characteristics also was determined. Annual population-based rates of antibiotic prescriptions for wheezing episodes were modeled by age and antibiotic class, using general estimating equations. The odds ratio for receiving an antibiotic prescription according to child demographics and physician factors was determined from hierarchical linear modeling.

Results. The antibiotic prescription rate for wheezing decreased by 28% from 708 prescriptions per 1000 children with asthma in 1995 to 511 prescriptions in 2001. Fifteen-fold increases in use were observed for broader spectrum macrolides in preschool children. Twenty-three percent of physician visits for wheezing resulted in an immediate antibiotic prescription, but this percentage increased to 64% for antibiotics that were received within 7 days of the episode. General practitioners prescribed antibiotics more often than did pediatricians. Physicians who were not trained in Canada or the United States were 40% more likely to prescribe antibiotics than their counterparts.

CONCLUSIONS. Antibiotic use for wheezing in children declined in the 1990s, but the increased use of broader spectrum macrolides has implications for antibiotic resistance. A link between antibiotic prescribing and physician specialty and location of training identifies opportunities for intervention.

Key Words: antibiotics • children • asthma • macrolides • trends • physician factors

Abbreviations: FY—fiscal year • NS—narrow-spectrum • BS—broader spectrum • OR—odds ratio • GP—general practitioner • CI—confidence interval

Increasing morbidity as a result of asthma and antibiotic resistance is a major public health concern. Asthma treatment guidelines state that antibiotics are unnecessary in the treatment of acute asthma.1,2 This is because respiratory viruses are detected in 80% of asthma exacerbations in children.3 Despite this evidence, it is estimated that 15% to 25% of children receive antibiotics for episodes of wheezing or asthma.4–8 Similar to the general trend in antibiotic use among children, antibiotics were used increasingly more often to treat acute asthma in the North American setting in the late 1980s.8,9 The 1990s witnessed a reversal of the trend in overall antibiotic use.10,11 However, antibiotic resistance has increased, and certain environments, such as child care centers, have been identified as reservoirs of antibiotic resistance.12,13 A recent evaluation of a primary care setting in Canada reported that 64% of children with asthma had received an antibiotic prescription for a respiratory tract infection, in comparison with 2% of children without asthma.14 We previously reported that asthma/bronchitis diagnoses accounted for 14% of antibiotic prescriptions for respiratory tract infections.15 Could children with asthma be a reservoir for antibiotic resistance? There is no information on trends in antibiotic use to treat wheezing in the 1990s. Therefore, we undertook such an evaluation in a population of Canadian children with asthma, with the added objective of studying physician determinants of antibiotic use in this population.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This was a descriptive study of the trends in antibiotic prescription use for wheezing episodes in a complete population of children with asthma during the period fiscal year (FY) 1995 to FY2001. A secondary analysis was conducted to identify physician and household determinants of antibiotic use for wheeze in a subgroup of children for whom these data were available for the period FY1996 to FY2000.

The study protocol was approved by the Manitoba Human Research Ethics Board and Health Information Privacy Committee. Data sources for this research were the population-based, health care administrative and prescription databases of the Manitoba Health Services Insurance Plan, which represent all encounters of every Manitoban with the health care system. The data sources included registration files; International Classification of Disease, Ninth Revision, Clinical Modification diagnostic codes and physician information from physician reimbursement claims and hospital discharge abstracts; and prescriptions that were dispensed in retail pharmacies. The Manitoba Health Services Insurance Plan's databases have good reliability and validity for describing population prescription drug use and disease prevalence.16,17

The primary outcome was dispensing of an antibiotic prescription within 2 days after an ambulatory physician visit for a wheezing episode in children with asthma. Asthma was identified from health care database records as18 at least 1 physician visit or hospitalization for asthma or at least 1 prescription for an asthma drug (eg, bronchodilator, inhaled corticosteroid/chromone, leukotriene receptor antagonist). In the absence of specific International Classification of Disease, Ninth Revision, Clinical Modification diagnosis codes for wheezing symptoms, diagnosis codes for asthma, bronchitis, and bronchiolitis were selected on the basis of the validity of their use in health care record studies to measure asthma exacerbations or recent wheeze.19–22

Population-based rates for antibiotic use in wheezing, defined as the annual number of antibiotic prescriptions dispensed per 1000 children with asthma, were determined. Rates were modeled as a function of year, antibiotic class, and age using general estimating equations to account for the dependence of antibiotic data between successive study years.23 Antibiotic classes included narrow-spectrum (NS) penicillins (penicillin and cloxacillin), broader spectrum (BS) penicillins, NS cephalosporins (cephalexin and cefadroxil), BS cephalosporins, NS macrolides (erythromycin), BS macrolides (azithromycin and clarithromycin), sulfonamides, and other antibiotics. A linear contrast was used to test for absolute differences in rates between FY1995 and FY2001 at the 95% level of confidence.

The likelihood (odds ratio [OR]) of receiving an antibiotic prescription for a wheezing episode according to child age and gender, household income, year, season, and physician factors was determined.24–28 Physician factors included age, gender, location of training (medical school in Canada/United States versus not), specialty (general practitioner [GP], pediatrician, and specialist), years of practice (<20 years versus ≥20 years), hospital affiliation (physician identified as treating physician in hospital database), and type of practice (solo versus group). A solo practitioner was defined when reimbursement claims were received from 1 location and no reimbursement claims from other physicians were received from this location.29 Recognizing the multilevel structure of the data, hierarchical linear modeling was pursued to determine the ORs,30 using HLM2 Version 5.0 (Scientific Software International, Inc, Lincolnwood, IL). Child physician visits were nested within physicians, and the most parsimonious model was selected at a significance level of P < .05. Population-based rates and multivariate analyses were repeated for the outcome of antibiotic dispensing within 7 days of the wheezing episode.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The population-based prescription rate for all antibiotics that were used in the treatment of wheezing declined by 28% from 708 per 1000 children with asthma in FY1995 to 511 prescriptions per 1000 in FY2001, which was statistically significantly lower than the 1995 rate (Table 1). The 2001 prescription rate for antibiotics that were dispensed within 7 days of the wheezing episode was 1309 prescriptions per 1000 children. Statistically significant decreases in population-based prescription rates were observed for most of the antibiotic classes, with the percentage decrease being greatest in the sulfonamide (80%) and NS macrolide (62%) class. There was 1 exception to the declining trend in antibiotic use: BS macrolide prescriptions. Their rate rose 8-fold, from 16 prescriptions per 1000 in FY1995 to 133 prescriptions per 1000 in FY2001. The total antibiotic prescription rate for wheezing episodes decreased in children of all ages (Table 2), with the greatest decline observed in infants. However, along with preschool children, infants had the highest rates of antibiotic use in FY1995 and FY2001. Preschool children experienced a 15-fold increase in the prescription of BS macrolides during the 7-year evaluation period.


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  		TABLE 1 Antibiotic Prescriptions for Wheezing per 1000 Children (95% CI) by Year and Antibiotic Class, All Ages

 

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  		TABLE 2 Antibiotic Prescriptions for Wheezing per 1000 Children (95% CI) by Age Group for Total Antibiotics and BS Macrolides, FY1995 Versus FY2001

 
Determinants of antibiotic use were assessed in 7791 children with 32746 visits for wheezing to 1099 physicians during the period FY1996 to FY2000. The average child age was 9.0 years (SD: 5.5 years), and there was a predominance of boys (56%). Seventy-seven percent of children lived in households with annual incomes <$40000 Canadian. Physicians were predominantly male (71%) and aged <50 years (70%). More than half had received training in Canada and the United States, 86% were GPs, 8% were pediatricians, 6% were specialists, and 91% had a hospital affiliation. Eighty percent had practiced for <20 years, and 92% were part of a group practice. The highest proportion of physician visits for wheezing occurred in 5- to 9-year-old children; children who lived in the lowest income households; and children who were seen by GPs and by physicians with <20 years of practice, group practices, and hospital affiliations (Tables 3 and 4). Forty-two percent of child visits to physicians for wheezing symptoms occurred during the winter months, and 22% occurred during the fall months.


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  		TABLE 3 Antibiotic Prescription Use by Child, Visit, and Household Characteristics, FY1996 to FY2000

 

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  		TABLE 4 Antibiotic Prescription Use by Physician Characteristics, FY1996 to FY2000

 
Twenty-three percent of physician visits for wheezing during FY1996 to FY2000 resulted in immediate dispensing (within 2 days) of an antibiotic prescription. This proportion increased to 64% when the time interval for the antibiotic prescription was extended to 7 days after the physician visit. There were no differences between study years. Immediate dispensing of an antibiotic for wheeze was close to 30% in preschool children and children who were seen by GPs and physicians who were not trained in Canada or the United States (Tables 3 and 4). Antibiotics were dispensed in 38% of wheezing visits to physicians without hospital affiliations. Findings from the multivariate HLM logistic regression (Table 5) showed that younger children and those with physician visits during the winter were the most likely to receive an antibiotic for wheezing. GPs were twice as likely as pediatricians to prescribe antibiotics (OR: 2.1; 95% confidence interval [CI]: 1.82–2.53). The OR for an antibiotic prescription was 1.38 (95% CI: 1.22–1.55) for a physician who was not trained in Canada or the United States. Furthermore, antibiotics for wheezing were more likely to be prescribed by older physicians. All likelihood ratios were independent of each other. Similar multivariate findings were obtained when the outcome was an antibiotic prescription that was dispensed within 7 days of the physician visit, with 1 exception: female children were more likely to receive antibiotic prescriptions at later time periods (OR: 1.11; 95% CI: 1.02–1.21).


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  		TABLE 5 Likelihood of Receiving an Antibiotic Prescription (≤2 Days) for a Wheezing Episode by Child/Physician Factors

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have documented evidence in a complete population of Manitoba children with asthma that the rate of antibiotic prescription use for wheezing had declined by more than one quarter, from a rate of 0.7 antibiotic prescriptions per child in FY1995 to 0.5 prescriptions in FY2001. The sulfonamide and NS macrolide classes of antibiotics declined the most. These findings parallel decreases in antibiotic use in North American children.10,11,15 However, our study documented that 23% of physician visits for wheezing resulted in an immediate antibiotic prescription, and this percentage increased to 64% for antibiotics that were received within 7 days of the episode. Neither of these percentages had changed during the period FY1996 to FY2000, indicating that the observed decrease in the volume of antibiotic prescriptions was attributable to a decrease in physician visits for wheezing, rather than a decreased likelihood of physician prescribing. This prescribing was counter to asthma treatment guidelines in the 1990s, which did not recommend the routine use of antibiotics for asthma exacerbation.31,32 In children with asthma, this represents exposure to antibiotics over and beyond receiving antibiotics for common childhood conditions, such as acute otitis media.

Moreover, our study documented that dispensing rates for BS macrolides in wheezing had increased. This is consistent with reported increases in use of these antibiotics across Canada and the United States, after their introduction on the market in the 1990s.12,33,34 BS macrolides are well tolerated and easy to use in the pediatric age group. Other antibiotic utilization studies also have reported significant macrolide use in people with asthma exacerbations.22 Although Chlamydia and Mycoplasma have been identified in children with acute episodes of wheezing, the role of these organisms in precipitating wheezing is unclear,35,36 and they are found much less frequently than rhinoviruses.37 Macrolides also have anti-inflammatory properties, but systematic reviews are inconclusive regarding their benefit in asthma.38 Therefore, there is no clear evidence to support the use of BS macrolides in asthma exacerbations without comorbidities, such as pneumonia.39 Our findings show that BS macrolide use increased by 15-fold in preschool children, the population that has experienced macrolide resistance in child care centers.12

The same extent of antibiotic use in children with asthma has been observed in other settings.4–8,14 We identified several physician characteristics in which this inappropriate prescribing occurred more often. Namely, GPs were more likely than pediatricians to prescribe an antibiotic for a wheezing episode, as were older physicians. These prescriber characteristics have been reported by others.4,22 We also reported that foreign-trained physicians were more likely than those who were trained in Canada and the United States to prescribe an antibiotic for wheezing.

There were other factors that predicted antibiotic prescribing. The winter season was associated with an increased likelihood of an antibiotic prescription. Although evidence indicates that wheezing in winter is more likely to be precipitated by viruses, these findings may represent physician concern about the likelihood of a bacterial infection.40 This concern may have been heightened with continued or worsening symptoms,41 as indicated by the higher rates of antibiotic prescriptions that were received within 7 days of the wheezing episode. Alternatively, the higher antibiotic prescription rate during this later period may represent appropriate treatment for asthma comorbidities, such as acute otitis media or pneumonia.

We were limited in our ability specifically to identify wheezing episodes in asthma but followed the method of other health care database studies by selecting diagnoses that most closely represented wheezing.21,22 Bronchitis and bronchiolitis present as wheezing symptoms and can precipitate the development of asthma or mimic asthma exacerbations.20,42,43 Although the majority of physician visits for asthma diagnoses are for asthma symptoms,19 some of the physician visits may have been for routine follow-up of asthma or for a concomitant infection, such as acute otitis media. A short (2-day) time frame after the physician visit increased the likelihood that the antibiotic was for the wheeze episode and not a subsequent infection, but secondary diagnoses were not available in the provincial physician visit data to identify co-infections. The highest rates of physician visits for wheeze conditions were during the fall and the winter, which follows the seasonal presentation of worsening asthma and suggests that exacerbation of disease was a more likely reason for the visit than routine reassessment.44 We used a database definition of asthma that we previously had validated but not in children who are younger than 5 years.18 Therefore, the possibility that we have reported antibiotic use in young children with bronchiolitis exists. This is not a study limitation because antibiotics are not recommended in bronchiolitis, because virtually all episodes are viral and serious bacterial infection is a rare event.45 In our study, an antibiotic was dispensed in 28% to 77% of wheezing episodes in this age group. The higher rate for antibiotic dispensing within 7 days after physician visit for wheeze may indicate appropriate antibiotic treatment for subsequent acute otitis media, the most common co-infection in children with bronchiolitis.46

The hazards of antibiotic use are widely known. Immediate outcomes of antibiotic use are the adverse effects and costs associated with therapy.26,47 Longer term, they include antibiotic resistance.48,49 However, in children with asthma, another hazard exists: the undermanagement of the disease. A child may receive several courses of antibiotics for wheezing before the initiation of bronchodilator therapy.50 A study of British schoolchildren documented that antibiotics had been prescribed without asthma treatment in 32% of children with persistent wheeze and 20% of children with acute asthma attacks.6 Our data suggest that female children may be at greater risk for this outcome. Williams et al51 also found that female children with asthma were more likely than male children to be treated with antibiotics. Female children with asthma also have been reported to be less likely to be treated with inhaled or oral corticosteroids.51,52

We have presented recent data on dispensed antibiotic prescriptions for wheezing in a complete population of children. The total number of antibiotics dispensed to children for wheezing has declined, but the proportion of episodes that are treated with antibiotics has remained the same. Furthermore, BS macrolides are being used increasingly more often, especially in infants and preschool children. The extent of this inappropriate antibiotic use in children with asthma clearly needs to addressed in Canadian asthma treatment guidelines, which currently do not provide recommendations on the role of antibiotics in asthma exacerbations.53 According to our findings, targeting dissemination of asthma treatment guidelines to family physicians and those who were not trained in Canada or the United States would be a beneficial intervention strategy.


   ACKNOWLEDGMENTS
 
This research was funded by the Canadian Population Health Initiative Operating Grant Program, Canadian Institute for Health Information.

We acknowledge the research assistant support of Sazzadal Khan.


   FOOTNOTES
 
Accepted Dec 21, 2005.

Address correspondence to Anita Kozyrskyj, PhD, Manitoba Centre for Health Policy, 408-727 McDermot Ave, Winnipeg, Manitoba, Canada R3E 3P5. E-mail: Kozyrsk{at}cc.umanitoba.ca

Data were obtained from the Population Health Research Data Repository at the Manitoba Centre for Health Policy, Winnipeg, Canada. The results and conclusions are those of the authors, and no official endorsement by Manitoba Health was intended or should be inferred.

The authors have indicated they have no financial relationships relevant to this article to disclose.


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