Evidence Report/Technology Assessment

Number 15

Prepared for:
Agency for Healthcare Research and Quality
U.S. Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852

http://www.ahrq.gov/

Contract No. 290-97-0001

Prepared by:
Southern California Evidence-based Practice Center
Michael Marcy, M.D.
Principal Investigator


Glenn Takata, M.D., M.S.
Linda S. Chan, Ph.D.
Paul Shekelle, M.D., Ph.D.
Wilbert Mason, M.D., M.P.H.
Laura Wachsman, M.D.
Richard Ernst, Ph.D.
Joel W. Hay, Ph.D.
Pamal M. Corley, M.S.L.S.
Tricia Morphew, M.S.
Emily Ramicone, M.S.
Connie Nicholson
Investigators

AHRQ Publication No. 01-E010

May 2001

ISBN 1-58763-027-3
ISSN 1530-4396

On December 6, 1999, under Public Law 106-129, the Agency for Health Care Policy and Research (AHCPR) was reauthorized and renamed the Agency for Healthcare Research and Quality (AHRQ). The law authorizes AHRQ to continue its research on the cost, quality, and outcomes of health care and expands its role to improve patient safety and address medical errors.

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

John M. Eisenberg, M.D.	Douglas B. Kamerow, M.D.
Director	Director, Center for Practice and
Agency for Healthcare Research and Quality	Technology Assessment
	Agency for Healthcare Research and Quality

The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.

Our objective with this report was to analyze the evidence on the initial management of uncomplicated acute otitis media (AOM) in children. We assessed three 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 such as: (1) amoxicillin or trimethoprim-sulfamethoxazole vs. other antibiotics, (2) oral fluoroquinolones, (3) >60 mg/kg/day amoxicillin or amoxicillin-clavulanate vs. 40 mg/kg/day, (4) high-dose amoxicillin therapy twice a day vs. three times a day, and (5) short-term vs. long-term antibiotic therapy?

The technical experts and project staff developed a literature search strategy that used MEDLINE, the Cochrane Library, HealthSTAR, International Pharmaceutical Abstracts, Cumulative Index to Nursing & Allied Health Literature, BIOSIS, and EMBASE. Headings included "om" (otitis media), "mastoiditis," "om w/effusion," "om, suppurative" with the subheading "drug therapy," and "anti-infective agents," including "antibiotics" and "other drugs." Text words included otitis media, antibiotic, antimicrobial, antibacterial, specific antibiotic names and natural history, natural course, untreated, spontaneous, and self-limited for the natural history search. Additional articles were identified by review of reference lists in proceedings, published articles, reports, and guidelines.

The selection criteria included human studies addressing AOM in children age 4 weeks to 18 years. Excluded were studies on patients with immunodeficiencies or craniofacial deficiencies, including cleft palate. Randomized clinical trials and cohort studies were included for the question on natural history. Randomized controlled trials were used to address the questions on antibiotic effectiveness.

Two physician reviewers independently evaluated articles and abstracted data. They excluded articles that did not address any of the key questions or that had unabstractable data. They assessed the quality of the studies. Project staff developed evidence tables using the abstracted data. Meta-analyses were performed as appropriate. Twenty-four experts and consumers critiqued the draft of this evidence report.

Clinical failure was defined generally as the failure to resolve or improve clinical signs and symptoms at specific time intervals. In children with AOM not initially treated with antibiotics, the reported rate of clinical failure at 24-48 hours was 7.7 percent in one study and at 24-72 hours was 26 percent in another study. The pooled estimated failure rate at 1-7 days was 18.9 percent and was 22.2 percent at 4-7 days. Compared with this failure rate, children treated with ampicillin or amoxicillin showed a reduction in clinical failure at 2-7 days of 12.3 percent. This result generally was 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 failure. The pooled comparisons of specific antibiotic regimens showed no difference in clinical failure rates. Adverse effects, primarily gastrointestinal, were more common in children on cefixime than those on ampicillin or amoxicillin and more common in children on amoxicillin-clavulanate (original formulation) than those on azithromycin.

There is a wide range of reported clinical failure rates in the first week in children with AOM who are not treated with antibiotics. The pooled estimates indicate that a majority of these children have clinical resolution within the first week after presentation. These studies, which generally are of small sample size, report few episodes of suppurative complications, regardless of antibiotic treatment. In general, the children in the natural history studies had close followup. Antibiotic treatment with ampicillin or amoxicillin produces a statistically significant improvement in failure rates compared with no antibiotic treatment of AOM. We found no difference in clinical failure rates in the antibiotic regimens assessed. Since we were unable to do subgroup analysis in the meta-analytic comparisons, we cannot generalize those findings to children in specific age groups, such as younger than or older than 2 years of age, or by otitis-prone status. Several studies suggest greater caution be taken with children younger than 2 years old.

Randomized controlled studies still are needed to address definitively the initial key questions. Future research should focus on: (1) establishing uniform definitions of AOM and relevant outcomes, (2) establishing uniform diagnostic criteria, (3) strengthening internal and external validity, (4) addressing relevant influencing factors such as age and otitis-prone state, and (5) measuring long-term as well as short-term outcomes. Studies also should be of sufficient power to establish differences in antibiotic efficacy. In addition, future studies should address the bacterial resistance issue.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Marcy M, Takata G, Shekelle P, et al. Management of Acute Otitis Media. Evidence Report/Technology Assessment No. 15 (Prepared by the Southern California Evidence-based Practice Center under Contract No. 290-97-0001). AHRQ Publication No. 01-E010. Rockville, MD: Agency for Healthcare Research and Quality. May 2001.

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, 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.

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?
• What is the relative effectiveness of specific antibiotic regimens?

The regimens we analyzed were:

(1) amoxicillin or trimethoprim-sulfamethoxazole vs. other antibiotics,

(2) oral fluoroquinolones,

(3) 60 mg or higher per kg/day of amoxicillin or amoxicillin-clavulanate vs. the standard 40 mg per kg/day,

(4) high-dose amoxicillin therapy twice a day vs. three times a day, and

(5) 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, at 3 to 7 days, 7 to14 days, 14 days to 3 months, and after 3 months; presence or absence of adverse effects from antibiotic treatment; and 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.

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, and
• 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), and 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 focused 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 antibiotic 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 antibiotics 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.

• In children with AOM who were not initial treated with antibiotics, one study showed a clinical failure rate of 7.7 percent at 24 to 48 hours, and another study showed a failure rate of 26 percent at 24 to 72 hours -- that is, clinical resolution was 92.3 percent at 24 to 48 hours and 74 percent at 24 to 72 hours. The pooled estimate of failure at 1 to 7 days was 18.9 percent (95 percent confidence intervals, 9.9 percent and 28.0 percent) and at 4 to 7 days was 22.2 percent (95 percent confidence intervals, 10.1 percent and 34.3 percent).
• A previous information synthesis estimated that 59 percent (95 percent confidence intervals, 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 intervals, 84 percent and 89 percent) of children had resolution of pain and fever within 2 to 3 days, and 88 percent (95 percent confidence intervals, 85 percent and 91 percent) of children had resolution of pain and fever within 4 to 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.

• Meta-analysis demonstrated a reduction in the clinical failure rate within 2 to 7 days of 12.3 percent (95 percent confidence intervals, 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 to 7 days, contralateral otitis media and 7- to14-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 to 7 days, tympanic membrane perforation, vomiting/diarrhea/rash, 1-month tympanometry, or recurrent AOM.

• 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 to 10 day amoxicillin therapy and azithromycin therapy for less than 5 days with 7 to 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 to 10 day amoxicillin-clavulanate had a 19.2 percent (95 percent confidence intervals, 9.2 percent and 29.2 percent) greater rate of overall adverse effects and a 12.9 percent (95 percent confidence intervals, 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.)

• 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 of the 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.

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: (1) establish uniform definitions of AOM and relevant clinical, bacteriologic, and societal outcomes; (2) establish uniform diagnostic criteria for AOM; (3) strengthen internal and external validity; (4) address relevant influencing factors, such as age and otitis-prone state, and (5) 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.