Evidence Report/Technology Assessment: Number 15
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Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of the Full Report
The objective of this report was to analyze the evidence on the initial management of uncomplicated acute otitis media (AOM) in children. AOM is one of the most common diagnoses in children. Data from the National Ambulatory Medical Care Surveys (NAMCS), which did not differentiate between AOM and otitis media with effusion, indicated that the number of office visits for AOM increased more than two-fold from 1975 to 1990.
Gates (1996a) believed that the majority of these cases represented AOM. Based on national data from NAMCS and the National Hospital Ambulatory Medical Care Surveys, and several assumptions detailed in Appendix A of the report, we estimated that 5.18 million episodes of AOM occurred in 1995 at a cost of approximately $2.98 billion, including direct and indirect costs and the costs of sequelae such as otitis media with effusion and chronic middle ear infection. These estimates suggest that increased effectiveness in treating AOM could achieve significant national cost savings.
AOM was defined by the Technical Expert Panel as the presence of middle-ear effusion in conjunction with the rapid onset of one or more signs or symptoms of inflammation of the middle ear. Uncomplicated AOM was defined as AOM that is limited to the middle ear cleft.
An episode of uncomplicated AOM was considered distinct from a previous episode of AOM and was eligible for initial treatment if the most recent course of antibiotics ended 4 weeks prior to the episode of AOM in question, or if there was documentation by an examiner that a prior episode of AOM had been cleared.
Various medical and surgical treatments have been used for AOM. There is controversy about the need for antibiotics, particularly in children older than 6 months of age with uncomplicated AOM. It is routine to use antibiotics for AOM in the United States, whereas in the Netherlands the standard practice is to observe selected children older than 2 years of age for 48 hours and selected children age 6 months to 2 years for 24 hours before initiating antibiotics. Antibiotics are prescribed if clinical resolution does not occur during the observation period.
The presence of alternative treatment paradigms of questioned effectiveness suggests that an evidence-based analysis on the management of AOM is needed to determine the efficacy of antibiotic therapy.
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Reporting the Evidence
The Technical Expert Panel limited the scope of this evidence report to three key clinical questions:
- What is the natural history of AOM without antibiotic treatment?
- Are antibiotics effective in preventing clinical failure?
- And what is the relative effectiveness of specific antibiotic regimens?
The regimens we analyzed were:
- Amoxicillin or trimethoprim-sulfamethoxazole vs. other antibiotics.
- Oral fluoroquinolones.
- 60 mg or higher per kg/day of amoxicillin or amoxicillin-clavulanate vs. the standard 40 mg per kg/day.
- High-dose amoxicillin therapy twice a day vs. three times a day.
- Short-term vs. long-term antibiotic therapy.
The Technical Expert Panel decided that this systematic review would focus on children ages 4 weeks to 18 years who had uncomplicated AOM and were seeking initial treatment. The major outcomes included:
- Presence or absence of signs and symptoms within 48 hours, 3 to 7 days, 7 to 14 days, 14 days to 3 months, and after 3 months.
- Presence or absence of adverse effects from antibiotic treatment.
- Presence or absence of bacteria and/or resistant bacteria.
Of a total of 41 factors that the Technical Expert Panel felt could influence outcomes apart from antibiotics, the panel ranked age (younger and older than 2 years) and otitis-prone state as the two most important factors. The otitis-prone child was defined as the child who had three or more episodes of AOM in a 6-month period or four or more episodes of AOM in a 12-month period.
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An 11-member Technical Expert Panel consisting of clinical experts, a consumer, and a representative of a managed care organization convened to:
- Advise the project in the ranking of proposed key questions and influencing factors.
- Guide the development of the scope and definition of AOM.
- Advise in development of the search strategy.
- Review and comment on the analysis plan.
The Technical Expert Panel and project staff developed a literature search strategy. The initial strategy was developed for MEDLINE® and was customized for other databases. Project staff searched:
- MEDLINE® (1966-March 1999).
- The Cochrane Library (through March 1999).
- HealthSTAR (1975-March 1999).
- International Pharmaceutical Abstracts (1970-March 1999).
- The Cumulative Index to Nursing & Allied Health Literature (1982-March 1999).
- BIOSIS (1970-March 1999).
- EMBASE (1980-March 1999).
Additional articles were identified by review of reference lists in proceedings, published articles, reports, and guidelines.
The initial module of search statements included an explode of om (otitis media), which included the headings om, mastoiditis, om w/ effusion, and om, suppurative with the subheading drug therapy. The next module included the explode of om with om as a text word. The anti-infectives module used an explode of the mesh heading for anti-infective agents, including antibiotics and other drug groups, and the text words antibiotic, antimicrobial, antibacterial, and specific antibiotic names.
Combinations of these modules were used for the literature search. The search was limited to human or undesignated studies and to infant, child, preschool, adolescence, or undesignated subjects. For the natural history search, natural history, natural course, untreated, spontaneous, and self-limited were added as keywords.
Two physicians independently screened all titles and/or abstracts for potential inclusion, evaluated the quality of the articles, and abstracted data from full-length articles onto predesigned forms. The selection criteria included human studies that addressed a key question about AOM in children ages 4 weeks to 18 years. Excluded were case reports, editorials, letters, reviews, practice guidelines, and studies on patients with immunodeficiencies or craniofacial deficiencies, including cleft palate.
Randomized clinical trials and prospective and retrospective comparative cohort studies were included for the key question on natural history. Only randomized controlled trials were used to address the key questions on the effectiveness of antibiotics. The physician reviewers assessed the quality of controlled trials by using an established tool that focuses on randomization, blinding, and reporting of subject withdrawals. They also noted approximation to the diagnostic criteria for AOM established by the Technical Expert Panel.
A physician reviewer also reviewed articles in 13 non-English languages with the assistance of a translator. An initial review of 97 non-English-language articles yielded only two eligible studies, both of which already were known to the project staff. Based on this outcome, the Technical Expert Panel advised the project staff to discontinue further screening of non-English-language citations. Based on peer reviewers' suggestions, the remaining five Dutch and Scandinavian articles were reviewed and no additional studies were found.
Meta-analyses were performed to determine the effectiveness of antibiotics vs. placebo or observational treatment of uncomplicated AOM and to determine the effectiveness of particular antibiotic regimens. Comparisons were established based on the type of antibiotic and the outcome variable under consideration. The technical experts decided to establish comparison groups by individual antibiotic, as this best fit the information required for clinical practice. A meta-analysis was performed for each comparison with three or more randomized controlled studies. Heterogeneity was measured for all meta-analyses, and a random effects model was used to estimate the absolute rate differences.
Although subgroup and sensitivity analyses were initially planned based on age of the subject, otitis-prone status of the subject, study-design quality, and approximation to the Technical Expert Panel's diagnostic criteria for AOM, they could not be performed because an insufficient number of studies addressed these factors or because there was an insufficient number of studies within a comparison group.
This evidence report was critiqued by the Technical Expert Panel as well as a 25-member peer-review panel consisting of content experts, consumers, representatives of managed care organizations, an expert in pediatric pharmacology, and methodologists. All comments received from these individuals were reviewed and acted upon as appropriate with documentation in Appendix J of the report.
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Natural History of AOM
- In children with AOM who were not initially treated with antibiotics, one study showed a clinical failure rate of 7.7 percent at 24-48 hours, and another study showed a failure rate of 26 percent at 24-72 hours—that is, clinical resolution was 92.3 percent at 24-48 hours and 74 percent at 24-72 hours. The pooled estimate of failure at 1-7 days was 18.9 percent (95 percent confidence limits, 9.9 percent and 28.0 percent) and at 4-7 days was 22.2 percent (95 percent confidence limits, 10.1 percent and 34.3 percent).
- A previous information synthesis estimated that 59 percent (95 percent confidence limits, 53 percent and 65 percent) of children not treated with antibiotics had resolution of pain and fever within 24 hours of diagnosis of AOM, 87 percent (95 percent confidence limits, 84 percent and 89 percent) of children had resolution of pain and fever within 2-3 days, and 88 percent (95 percent confidence limits, 85 percent and 91 percent) of children had resolution of pain and fever within 4-7 days.
- The available evidence on natural history of AOM shows that in studies with close followup, few episodes of mastoiditis or other suppurative complications are reported in children with AOM who are not treated initially with antibiotics.
Effects of Antibiotics on AOM
- Meta-analysis demonstrated a reduction in the clinical failure rate within 2 to 7 days of 12.3 percent (95 percent confidence limits, 2.8 percent and 21.8 percent) in favor of ampicillin or amoxicillin therapy compared with placebo or observational treatment. This result was generally robust to sensitivity analysis. Eight children with AOM would need to be treated with ampicillin or amoxicillin rather than no antibiotic treatment to avoid a case of clinical failure.
- Previous meta-analyses have demonstrated minimal- to-modest benefits of antibiotics compared with observational intervention without antibiotics during the initial treatment of AOM for the following outcomes:
- Pain and fever resolution at 2 days.
- Pain resolution at 2-7 days.
- Contralateral otitis media.
- 7- to 14-day clinical resolution rate.
The following outcomes did not appear to be affected by antibiotic use:
- Pain resolution at 24 hours.
- Pain and fever resolution at 4-7 days.
- Tympanic membrane perforation, vomiting/diarrhea/rash.
- 1-month tympanometry.
- Recurrent AOM.
Relative Effects of Different Antibiotic Regimens
- Meta-analyses did not demonstrate a significant rate difference in clinical failure rates in children with AOM treated with ampicillin or amoxicillin compared with children treated with penicillin, cefaclor, or cefixime.
- Meta-analysis did not demonstrate a significant difference in clinical failure rates in children treated with trimethoprim-sulfamethoxazole compared with children treated with cefaclor for AOM.
- Meta-analysis demonstrated that children treated with cefixime had an 8.4 percent greater rate of diarrhea than children treated with ampicillin or amoxicillin. Twelve children with AOM would need to be treated with ampicillin or amoxicillin rather than cefixime to avoid a case of diarrhea.
- No comment can be made on the effect of oral fluoroquinolones compared with other antibiotics because no comparative, randomized controlled trials were found that addressed this question.
- Although not establishing equivalency of effect, a single study demonstrated no difference in clinical effect of high-dose amoxicillin-clavulanate vs. standard-dose amoxicillin-clavulanate.
- Although not establishing equivalency of effect, a single study did not demonstrate a difference in clinical effect of taking high-dose amoxicillin two times a day vs. three times a day.
- Meta-analysis did not demonstrate a difference in clinical effect between short-duration therapy and long-duration therapy when comparing single-dose ceftriaxone therapy with 7-10-day amoxicillin therapy and azithromycin therapy for less than 5 days with 7-10-day amoxicillin-clavulanate therapy.
- A previous meta-analysis demonstrated that short-acting oral antibiotic therapy of less than 2 days was not as effective as therapy lasting 7 days or longer.
- Meta-analysis demonstrated that children treated with 7-10-day amoxicillin-clavulanate had a 19.2 percent (95 percent confidence limits, 9.2 percent and 29.2 percent) greater rate of overall adverse effects and 12.9 percent (95 percent confidence limits, 4.5 percent and 21.2 percent) greater rate of gastrointestinal adverse effects than children treated with 5-day azithromycin.
- Eight children would need to be treated with azithromycin rather than amoxicillin-clavulanate to avoid a gastrointestinal adverse event. (Although not reported in the studies, the clavulanate concentration was most likely 31.25 mg per 125 mg of amoxicillin, i.e., original formulation.)
Limitations of the Literature
- The diagnostic criteria for AOM were not uniform across studies.
- Although some studies were of high quality, about one-half of the studies were not of adequate quality.
- The AOM outcomes varied among studies, and the definition of common outcomes such as clinical failure were not uniform. This inconsistency made it difficult to compare results across studies.
- The power of the studies to detect a difference appeared to be insufficient in most cases, although this was less important because the treatment effect sizes were generally less than 10 percent.
- Although many studies had significant numbers of children younger and older than age 2 years, we could not do subgroup analysis because most of the studies did not report outcome by age. We were, therefore, unable to focus the findings of this study to children in specific age groups. Several studies suggest that greater caution should be taken with children younger than age 2 years; however, these studies do not answer this question definitively.
- Because most studies did not report outcomes by otitis-prone status, we were unable to do subgroup analysis by this influencing factor.
- Based on the exclusion factors of the investigations used in this analysis, the study findings are most applicable to children without comorbidities and with AOM of lesser severity.
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Randomized controlled studies of high internal validity and adequate generalizability are needed to adequately address the key clinical questions asked at the start of this systematic review, including the question of the role of antibiotics in the treatment of uncomplicated AOM. Placebo-controlled trials of adequate power with sufficient patient variation for subgroup analysis are needed. Close monitoring of patients in these studies with a priori plans for appropriate intervention should allay any concerns about suppurative complications and should be a focus of research.
Future research should:
- Establish uniform definitions of AOM and relevant, clinical, bacteriologic, and societal outcomes.
- Establish uniform diagnostic criteria for AOM.
- Strengthen internal and external validity.
- Address relevant influencing factors, such as age and otitis-prone state.
- Measure long-term as well as short-term outcomes.
Uniform definition and diagnostic criteria are needed to ensure that results across studies can be compared. Appropriate randomization and blinding methods would establish the internal validity of future research. Sufficient variation in future study populations in terms of influencing factors as well as sufficient number of cases may allow results to be applied more readily to specific patients or populations and to be generalized to other populations. Although not addressed in this evidence-based analysis, future research should consider the impact of bacterial resistance on AOM outcomes. Investigators should prioritize AOM outcomes based, in large part, on their importance to patients, their families, and society as a whole because they bear the burden of AOM.
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Availability of the Full Report
The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality by the socalepc.htm">Southern California Evidence-based Practice Center, Santa Monica, CA, under contract No. 290-97-0001. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 1-800-358-9295. Requestors should ask for Evidence Report/Technology Assessment No. 15, Management of Acute Otitis Media (AHRQ Publication No. 00-E010).
The Evidence Report is also online on the National Library of Medicine Bookshelf.
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AHRQ Publication Number 00-E008
Current as of June 2000