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PEDIATRICS Vol. 108 No. 2 August 2001, pp. 239-247

Evidence Assessment of Management of Acute Otitis Media: I. The Role of Antibiotics in Treatment of Uncomplicated Acute Otitis Media

Glenn S. Takata, MD*, §, Linda S. Chan, PhDDagger , §, Paul Shekelle, MD, PhDparallel , #, Sally C. Morton, PhD, #, Wilbert Mason, MD§, **, and S. Michael Marcy, MDDagger Dagger

From the * Division of General Pediatrics, Childrens Hospital, Los Angeles, California; Dagger  Division of Biostatistics & Outcomes Assessment, Los Angeles County and University of Southern California Medical Center, Los Angeles, California; § Center for Pediatric Health Outcomes Research, Department of Pediatrics, University of Southern California, Los Angeles, California; parallel  Health Services Research and Development Service, Greater Los Angeles Veterans' Affairs Healthcare System, Los Angeles, California;  Statistics Group, RAND, Santa Monica, California; # Southern California Evidence-Based Practice Center, RAND, Santa Monica, California; ** Division of Infectious Diseases, Childrens Hospital, Los Angeles, California; Dagger Dagger  Department of Pediatrics, Southern California Kaiser-Permanente Health Care Program, Panorama City, California.


    ABSTRACT
Top
Abstract
Methods
Results
Discussion
References

Context.  In 1995, >5 million episodes of acute otitis media (AOM) accounted for $3 billion in health care expenditures.

Objectives.  To synthesize the literature on the natural history of AOM, the effectiveness of antibiotic treatment in uncomplicated AOM, and the relative effectiveness of specific antibiotic regimens.

Data Sources.  Seven electronic databases for articles published between 1966 and March 1999 and reference lists in proceedings, published articles, reports, and guidelines.

Study Selection.  Two physicians independently assessed each article. Studies addressing AOM in children 4 weeks to 18 years old were included; those addressing children with immunodeficiencies or craniofacial abnormalities were excluded. Randomized, controlled trials (RCTs) were used to assess antibiotic effectiveness, and RCTs and cohort studies were used to assess the natural history of AOM. Among the 3491 citations identified, 80 (2.3%) met our inclusion criteria.

Data Extraction.  Two physicians independently abstracted data and assessed the quality of studies using a validated scale for RCTs and 8 quality components for cohort studies.

Data Synthesis.  Random-effects estimates of pooled absolute rate differences of outcomes were derived, and heterogeneity of both the rates and rate differences was assessed. Children with AOM not treated with antibiotics experienced a 1- to 7-day clinical failure rate of 19% (95% confidence interval: 0.10-0.28) and few suppurative complications. When patients were treated with amoxicillin, the 2- to 7-day clinical failure rate was reduced to 7%, a 12% (95% confidence interval: 0.04-0.20) reduction. Adverse effects, primarily gastrointestinal, were more common among children on cefixime than among those on ampicillin or amoxicillin. They were also more common among children on amoxicillin-clavulanate than among those on azithromycin.

Conclusions.  The majority of uncomplicated cases of AOM resolve spontaneously without apparent suppurative complications. Ampicillin or amoxicillin confers a limited therapeutic benefit. There is no evidence to support any particular antibiotic regimens as more effective at relieving symptoms. Certain antibiotics are more likely than others to cause diarrhea and other adverse events.  Key words:  otitis media, children, antibiotics.

The incidence of acute otitis media (AOM), one of the most common diagnoses among children, appears to be increasing. Data from the National Ambulatory Medical Care Surveys (NAMCS) indicate that the number of office visits for otitis media increased more than twofold from 1975 to 1990.1 Although the NAMCS does not differentiate between AOM and otitis media with effusion, the majority of these cases are believed to represent AOM.2,3 Using data from the NAMCS and the National Hospital Ambulatory Medical Care Surveys, we estimate that a minimum of 5.18 million episodes of AOM occurred in 1995, at a cost of approximately $2.98 billion.4 The use of antibiotics to treat uncomplicated AOM is controversial, particularly in children over 6 months old. Antibiotic treatment is routine in the United States, whereas the standard of practice in the Netherlands is to observe and provide symptomatic treatment for 24 to 48 hours before initiating antibiotic therapy.5 Although previous meta-analyses6-10 have examined various aspects of antibiotic use in AOM management, they focused primarily on aggregate antibiotic effects. An evidence assessment was conducted to review published literature on the natural history of AOM and the role of individual antibiotics in treating uncomplicated AOM in children. In Part II of this evidence assessment, we report the research gaps and priorities for future research identified during this process based on an evaluation of the diagnostic criteria, quality, factors influencing possible AOM outcomes, and outcomes in each study.

    METHODS
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Abstract
Methods
Results
Discussion
References

Our systematic review was guided by a panel of 11 multidisciplinary experts. The panel consisted of 2 general pediatricians with 1 also representing the health insurer perspective, 1 pediatric infectious disease specialist, 2 family physicians, 2 pediatric otolaryngologists, 1 nurse practitioner, 2 audiologists with 1 also representing speech pathology, and 1 consumer group representative. Eleven professional agencies nominated technical experts. From the pool of nominees, the project staff selected the panel of technical experts based on experience with AOM and time availability, balancing specialty area and geographic distribution.

This systematic review examined the following 3 questions:

  1. During an episode of uncomplicated AOM that is initially managed without any active intervention, what proportion of children experience the resolution of clinical signs and symptoms at different time intervals, and what is the incidence of acute suppurative complications?
  2. Is antibiotic therapy effective relative to no antibiotic therapy in the initial treatment of uncomplicated AOM?
  3. Does choice of antibiotic regimen make a difference in the initial treatment of uncomplicated AOM?

a.  Do antibiotics other than amoxicillin or trimethoprim-sulfamethoxazole add any marginal benefit relative to no antibiotic treatment?

b. Do oral fluoroquinolones add any marginal benefit?

c.  What is the value of using amoxicillin >= 60 mg/kg/d versus 40 mg/kg/d?

d.  What is the value of administering high-dose amoxicillin twice a day versus 3 times a day?

e.  What is the comparative effectiveness of short-term versus long-term antibiotic therapy?

Short-term and long-term refer to the course of therapy in terms of antibiotic administration, not the pharmacokinetics of the antibiotic.

Influencing Factors

Of a total of 41 different factors that could influence the clinical outcomes of AOM treatment, our analysis focused on 2 factors judged by the technical experts to be most important: age (under and over 2 years) and otitis-prone state. The otitis-prone child was defined as one who had experienced 3 or more episodes of AOM during a 6-month period or 4 or more episodes of AOM during a 12-month period.

Definitions

AOM was defined by the expert panel as the presence of middle-ear effusion in conjunction with the rapid onset of 1 or more signs or symptoms of inflammation of the middle ear. Middle-ear effusion could be demonstrated by tympanocentesis, the presence of liquid in the external ear canal as a result of tympanic membrane perforation, pneumatic otoscopy, tympanogram, or acoustic reflectometry. Rapid onset was defined as a lapse of <48 hours from the time the parent or guardian first noted signs or symptoms of AOM to the time of contact with the health system. Otalgia or pulling of the ear in an infant, otorrhea, irritability in the infant or toddler, and fever were all considered signs and symptoms of AOM under our diagnostic criteria.

Uncomplicated AOM was defined as AOM limited to the middle ear cleft. An episode of uncomplicated AOM was considered distinct from a previous episode of AOM and eligible for initial treatment if the most recent course of antibiotics had ended 4 weeks before the episode of AOM in question or if there was documented resolution of the previous episode of AOM.

Scope of the Analysis

Our evidence assessment was limited to children between the ages of 4 weeks and 18 years who were seeking treatment for uncomplicated AOM. The major outcomes included clinical signs and symptoms (eg, clinical failure as defined by the individual studies, presence of pain or fever, or presence of middle ear effusion) and the presence or absence of adverse effects from antibiotic treatment.

Data Sources

Our initial literature search strategy was developed for Medline and then 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), Cumulative Index to Nursing & Allied Health Literature (1982-March 1999), Biosis (1970-March 1999), and Embase (1980-March 1999). We included "gray literature" by reviewing abstracts, reference lists in proceedings, published articles, reports, and guidelines because their exclusion has been shown to be associated with bias in meta-analysis.11

A combination of 3 modules of search terms during our literature search was used. The initial module used an explosion of the term "om" (otitis media), which included the headings "om, mastoiditis," "om w/effusion," and "om, suppurative" with the subheading "drug therapy." The next module included an explosion of the terms "om" and "om" as text words. The anti-infectives module used an explosion of the mesh heading for anti-infective agents, which included antibiotics and other drug groups and the text words "antibiotic," "antimicrobial," "antibacterial," and specific antibiotic names. Our search was limited to human or undesignated studies and to infant, child, preschool, child or adolescence, or undesignated participants. For the natural history search, the key words "natural history," "natural course," "untreated," "spontaneous," and "self-limited" were added.

Study Selection

Two physicians independently screened all titles and abstracts for inclusion. Both randomized, controlled trials (RCTs) and cohort studies were accepted for the key question on natural history, whereas only RCTs were accepted for the key questions on antibiotic effectiveness. Case reports, editorials, letters, reviews, practice guidelines, and studies on patients with immunodeficiencies or craniofacial abnormalities, including cleft palate, were excluded.

Using the same patient and study criteria mentioned earlier, 2 physician reviewers independently rescreened each citation accepted during the initial screen using the full articles' contents. Any discrepancies in screening were resolved with the assistance of a senior investigator. A physician reviewer, using the same inclusion and exclusion criteria, also reviewed articles in non-English languages with the assistance of a translator. Non-English articles were not reviewed in duplicate. Studies were not masked at any stage.

Data Extraction

Two physicians independently extracted information about the interventions, inclusion and exclusion criteria, participant age and otitis-prone status, sample sizes, outcome measures, and results of each study. They independently evaluated the quality of each RCT using the Jadad scale, a validated tool that assesses randomization, blinding, and reporting of participant withdrawals.12 Eight criteria were used to evaluate the quality of the cohort studies: the presence or absence of a clear definition of the study cohort, an early inception point, a clear pathway of patient entry, complete follow-up, description of dropouts, objective outcome criteria, blind outcome assessment, and adjustment for extraneous factors. The reviewers also evaluated the adequacy of the definition of AOM in terms of middle-ear effusion, rapid onset, and signs and symptoms of AOM inflammation. Any discrepancies were resolved with the assistance of a senior investigator.

Data Synthesis

For all assessments, a minimum of 3 studies reporting common outcomes was required for conducting a meta-analysis. All meta-analyses used the DerSimonian and Laird random effects model,13 which incorporated both within- and between-study heterogeneity. For the natural history question, the pooled random effects incidence rates of the outcome measures were derived. Between any 2 antibiotic regimens, the absolute rate difference of clinical failures was used to evaluate their relative effectiveness. The effectiveness of individual antibiotics, rather than antibiotics as a class, was assessed because it would be more relevant to actual practice. The only a priori exception made was to group ampicillin with amoxicillin because of their great similarity. Heterogeneity of the studies was also studied, and funnel plots were used to assess publication bias, which would have been indicated by a lack of studies with statistically nonsignificant results.14

    RESULTS
Top
Abstract
Methods
Results
Discussion
References

Literature Search

Our search yielded a total of 3461 citations, of which 760 (22%) were accepted for additional review. Seventy-four of the 760 citations, excluding duplicates, were accepted for analysis. Of the 760 studies accepted for additional review, 487 were published in English and 273 were published in non-English languages. Of the 487 studies published in English, 72 (15%) met our inclusion criteria. Table 1 lists the reasons for rejecting the other studies. We later added 2 non-English studies,15,16 1 study identified from proceedings,17 4 studies from reference lists,18-21 and 1 study from recommendation of peer reviewers.22 Of the 74 RCTs, 39 (53%) had a Jadad score of 3 or higher (out of a possible score of 5); of the 6 cohort studies, 2 (33%) adequately addressed 4 of 8 quality criteria, and none addressed >4 criteria.

                              
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TABLE 1
Screening Results of Citations Retrieved From Electronic Databases

Natural History of AOM

Fifteen studies met our screening and inclusion criteria for the question on natural history.17-35 The study population and outcome specifications varied. Five studies reported the clinical failure rate at 1 to 7 days on a total of 739 children, yielding a pooled clinical failure rate of 19% (95% confidence interval [CI]: 0.10-0.28).23,25,28,30,31 Limiting clinical failure to 4 to 7 days produced a pooled estimate of 22% (95% CI: 0.10-0.34), which was based on 3 studies23,25,31 and 220 children. (In other words, 78% of children would have experienced clinical resolution within 4 to 7 days of diagnosis in the absence of any antibiotic therapy.) Few studies reported on clinical failure, pain, fever, and middle-ear effusion by age, and none of them reported these outcomes by otitis-prone status.

Nine studies from 8 citations provided data on the reported occurrence of mastoiditis and other suppurative complications in children who were not initially treated with antibiotics for AOM.17,19,20,2530-32,35 A total of 1211 children without antibiotic treatment yielded a pooled random effects estimate of the incidence of mastoiditis of 1 per 1000 (95% CI: 0-5).

Antibiotic Versus No Antibiotic

Table 2 presents the distribution of the number of studies (from 9 randomized trials) by individual antibiotic comparisons. Only 1 meta-analysis was performed comparing the use of ampicillin or amoxicillin versus placebo or observational treatment.2528-31 The clinical failure at 2 to 7 days of those receiving either ampicillin or amoxicillin was 12% (95% CI: 0.03-0.22) less than for those receiving placebo. Figure 1 presents the shrinkage plot showing the individual and pooled effect sizes of the absolute difference in clinical failure rate at 2 to 7 days between ampicillin or amoxicillin and placebo. In clinical terms, 8 children with AOM would have to be treated with ampicillin or amoxicillin to avoid clinical failure during this time frame. Sensitivity analyses did not affect the pooled estimate when we removed the 1 study29 that defined failure by tympanocentesis alone rather than by signs and symptoms or when we removed another study30 that used episodes, rather than participants, as its unit of analysis. The individual 2- to 7-day clinical failure rates of the 5 studies varied widely, as did their rate differences. Of the 5 studies in the meta-analysis, the percentage of children under 3 years old varied from 0% to 100%.

                              
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TABLE 2
Distribution of Studies for Antibiotic Versus No-Antibiotic Comparisons


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  		Fig. 1.   Shrinkage plot comparing clinical failure rate at 2 to 7 days between ampicillin or amoxicillin and placebo. The rectangle is the individual rate difference, and the horizontal line indicates its 95% CI. The diamond indicates the pooled estimate, and its width is the 95% CI.

Amoxicillin or Trimethoprim-Sulfamethoxazole Versus Other Antibiotics

Table 3 presents the distribution of the 34 studies27,3136-67 addressing this topic by different comparisons. There were sufficient data to perform meta-analyses on the following: penicillin V, cefaclor, and cefixime, individually, versus ampicillin or amoxicillin and cefaclor versus trimethoprim-sulfamethoxazole.

                              
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TABLE 3
Distribution of Studies for Amoxicillin or Trimethoprim-Sulfamethoxazole Versus Other Antibiotics Comparisons

The pooled clinical failure rate difference at 2 to 7 days from 3 studies31,37,49 comparing penicillin V with ampicillin or amoxicillin showed no significant difference. There were also no significant differences in the pooled clinical failure rate differences at 3 to 7 days from 4 studies39,46,49,61 and at 5 to 21 days from 5 studies39,46,49,56,61 comparing cefaclor with amoxicillin.

Analyses of the 10- to 15-day clinical failure rates in 4 studies,52,57,60,62 the 3- to 5-week recurrence of AOM in 3 studies,50,57,62 the incidence of vomiting in 5 studies,50,52,57,60,62 and incidence of rash in 4 studies50,52,57,60 showed no difference between cefixime and amoxicillin. The pooled diarrhea rate difference showed that children receiving cefixime had an 8% (95% CI: 0.04-0.13) higher diarrhea rate than children receiving amoxicillin. Figure 2 presents the shrinkage plot showing the individual and pooled effect sizes of this comparison. In clinical terms, 12 children would need to be treated with amoxicillin rather than cefixime to avoid a case of diarrhea.50,52,57,60,62 The incidence rates of diarrhea for the individual antibiotics varied widely, but the rate differences did not.


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  		Fig. 2.   Shrinkage plot comparing incidence of diarrhea between cefixime and ampicillin or amoxicillin. The rectangle is the individual rate difference, and the horizontal line indicates its 95% CI. The diamond indicates the pooled estimate, and its width is the 95% CI.

The pooled clinical failure rate difference at 14 days for 3 studies31,37,59 comparing cefaclor with trimethoprim-sulfamethoxazole showed no significant difference.

The remaining studies compared a multitude of antibiotics with ampicillin or amoxicillin or amoxicillin-clavulanate with trimethoprim-sulfamethoxazole. No difference in clinical failure rates was noted in these individual studies.

High-Dose Versus Standard-Dose Amoxicillin

The single study comparing high-dose to standard-dose amoxicillin-clavulanate demonstrated no difference in clinical response at the end of therapy, recurrence at 22 to 28 days, or adverse effects.68 The study reported a failure rate of 31% for high-dose therapy and 32% for the standard dosage at the end of therapy (power of 3%). The recurrence rate at days 22 to 28 was 16% for the high-dose therapy and 21% for the standard therapy (power of 19%). The adverse event rate was 50% for the high-dose therapy and 47% for the standard therapy (power of 7%).

Twice-a-Day Versus 3-Times-a-Day Amoxicillin

The single study comparing twice-a-day with 3-times-a-day high-dose amoxicillin demonstrated no significant clinical differences.69 The study reported a 15-day failure rate for bilateral disease of 11% for the twice-daily regimen and 9% for the 3-times-a-day regimen (power of 2%).

Short-Term Versus Long-Term Antibiotic Therapy

Table 4 presents the distribution of the 35 studies15,16,36,47,51,52,6770-97 in this group. Meta-analyses on the following comparisons of short-term versus long-term antibiotic therapy were performed: ceftriaxone (1 dose) versus amoxicillin (7-10 days), azithromycin (<5 days) versus amoxicillin-clavulanate (7-10 days), and azithromycin (5 days) versus amoxicillin-clavulanate (7-10 days). Analysis of 3 studies47,51,67 comparing ceftriaxone with amoxicillin showed no difference in 5- to 10-day clinical failure rates. Analysis of 10- to 14-day clinical failure rates in 5 studies71,79,89,91,95 comparing azithromycin with amoxicillin-clavulanate also revealed no significant differences.

                              
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TABLE 4
Distribution of Studies for Short-Term Versus Long-Term Antibiotic Therapy Comparisons

With regard to adverse events, 3 studies73,86,87 compared azithromycin with amoxicillin-clavulanate. Considering all types of adverse events, azithromycin was found to have a 19% (95% CI: 0.09-0.29) lower adverse event rate than amoxicillin-clavulanate. In clinical terms, 5 children would need to be treated with azithromycin rather than amoxicillin-clavulanate to avoid an adverse event. Considering gastrointestinal adverse events alone, children treated with azithromycin had 18% (95% CI: 0.08-0.28) fewer gastrointestinal problems than amoxicillin-clavulanate. Six children would need to be treated with azithromycin rather than amoxicillin-clavulanate to avoid a gastrointestinal adverse event. In both cases the amoxicillin-clavulanate adverse event rates and the rate differences varied widely.

Although many other short-term to long-term antibiotic therapy comparisons have been published, the majority of these studies demonstrated no difference in clinical failure rates.

Summary of Meta-analyses

Table 5 presents a summary of all meta-analyses. Subgroup analyses by age or otitis-prone status or sensitivity analyses by diagnostic criteria or study quality for these comparisons could not be done because most of the studies either did not stratify the findings by age or otitis-prone status and the number of studies for each level of study quality was inadequate.

                              
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TABLE 5
Summary of Meta-analyses

    DISCUSSION
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Abstract
Methods
Results
Discussion
References

Our assessment estimated that clinical signs and symptoms in a majority (78%) of children with AOM not initially treated with antibiotics resolved within 4 to 7 days. A previous evidence assessment estimated that 59% of children not initially treated with antibiotics experienced resolution of pain and fever within 24 hours, 87% experienced resolution within 2 to 3 days, and 88% experienced resolution within 4 to 7 days.9 This previous evidence assessment assumed that the resolution of pain or fever implied the resolution of the other, but we did not make this assumption in our assessment. Although we were unable to estimate the resolution of pain and fever for time periods earlier than 4 days after diagnosis, we are confident that our results more accurately reflect the data as originally reported in the studies. We also found, based on limited data, that in children not initially treated with antibiotics for uncomplicated AOM, about 1 in 1000 developed mastoiditis. The available studies indicated that the majority of cases of uncomplicated AOM resolved spontaneously without apparent suppurative complications. Our assessment indicated a modest benefit from amoxicillin or ampicillin in relieving clinical symptoms at 2 to 7 days. About 8 children with AOM would need to be treated with ampicillin or amoxicillin to reap the benefit of avoiding a clinical failure. A previous meta-analysis concluded that 7 children with AOM would need to be treated with antibiotics to prevent 1 clinical failure at 7 to 14 days.6 This previous meta-analysis included a study98 that was excluded from our meta-analysis because data on children could not be separated from that on adults. Our meta-analysis included 1 recent study34 that was not included in this previous meta-analysis. Furthermore, the estimates reported in this previous meta-analysis were derived from less rigorously defined clinical outcomes.

The same previous meta-analysis found no differences in the efficacy between a limited number of drugs and dosing regimens.6 We were able to assess the effects of an expanded list of drugs and dosing regimens. We found no evidence to support claims of superior efficacy for any particular drug or dosing regimen. We emphasize that the data were insufficient to make conclusions regarding any particular age group, in particular those younger than 2 years old.

Not studied in other meta-analyses was the comparison of adverse effects between individual antibiotics. Our assessment identified clinically important differences in adverse effects rates between individual antibiotics. Amoxicillin had lower diarrheal adverse events than cefixime. Azithromycin given for 5 days of treatment had fewer adverse events, particularly gastrointestinal, than 7 to 10 days of treatment with amoxicillin-clavulanate.

A randomized clinical trial99 comparing amoxicillin with placebo was published recently after the completion of our evidence assessment. It reported that persistent symptoms at day 4 occurred in 69 out of 117 children (59%) in the amoxicillin group and in 89 of 123 (72%) in the placebo group, a rate difference of 13% (95% CI: 0.1-0.25). These results are consistent with our meta-analyses, and adding this new study to our meta-analyses made little difference in our results for the natural history of AOM and the effectiveness of amoxicillin.

The validity of our results depends on several factors related to the quality of the independent studies in the evidence assessment. These factors include the quality of the study design and the criteria used for diagnosis of AOM, which we found deficient in a majority of the studies. In addition, the studies lacked uniformity in the definition of AOM outcomes. These issues are addressed in greater detail in Part II of our report. We cannot generalize our results because of the paucity of usable data in the literature on the factors of interest to our expert panel (ie, age and otitis-prone status). A previous meta-analysis100 attempted to evaluate the effectiveness of antibiotic treatment of AOM in children under 2 years old, but examination of the report reveals that data from 1 of the 4 studies28 included children older than 2 years old and in another of the studies101 the placebo group was treated with myringotomy.

Antibiotic resistance of bacteria associated with AOM is a growing concern.102-104 Era of a study might be a proxy for antibiotic resistance. In assessing the effect of antibiotic to no antibiotics, we assessed 3 studies conducted between 1965 and 197028-30 and 2 studies conducted between 1981 and 1990.25,30 Examining Fig 1, one observes that if the study demonstrating no effect of antibiotic28 was removed, the rate difference between the 1965-1970 era and the 1981-1990 era, when antibiotic resistance would be expected to be more common, would decrease. This observation, if it could be confirmed, might support the hypothesis that resistance to ampicillin or amoxicillin may be an important factor in AOM outcome. Thus far, the majority of studies did not address this issue. We believe that bacterial antibiotic resistance should be addressed in future studies both as a factor influencing AOM outcome and as an outcome of antibiotic use in AOM.

The evidence assessed in this study supports that the majority of uncomplicated cases of AOM resolve spontaneously without apparent suppurative complications, that treating AOM with ampicillin or amoxicillin confers a limited therapeutic benefit, that there are no data to support as superior any particular antibiotic at relieving symptoms, and that certain antibiotics are more likely than others to cause diarrhea and other adverse events. These findings must be interpreted with caution in light of the apparent weaknesses in the evidence assessed.

    ACKNOWLEDGMENTS

This article is based on research conducted by the Southern California Evidence-Based Practice Center under contract with the Agency for Healthcare Research and Quality ([AHRQ], Contract No. 290-97-0001). We are very grateful to our project staff, partners, technical experts, and peer reviewers for their tireless efforts and superb contributions and to the Agency for Healthcare Research and Quality for its technical support and for funding this project.

    FOOTNOTES

The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the US Department of Health and Human Services.

Received for publication Aug 22, 2000; accepted Nov 21, 2000.

Reprint requests to (G.S.T.) Childrens Hospital Los Angeles, 4650 Sunset Blvd, MS 76, Los Angeles, CA 90027. E-mail: gtakata{at}chla.usc.edu

    ABBREVIATIONS

AOM, acute otitis media; NAMCS, National Ambulatory Medical Care Surveys; RCT, randomized, controlled trial; CI, confidence interval.

    REFERENCES
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Abstract
Methods
Results
Discussion
References
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