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Clinical Review | Clinician's Corner

Diagnosis, Microbial Epidemiology, and Antibiotic Treatment of Acute Otitis Media in Children:  A Systematic Review FREE

Tumaini R. Coker, MD, MBA; Linda S. Chan, PhD; Sydne J. Newberry, PhD; Mary Ann Limbos, MD, MPH; Marika J. Suttorp, MS; Paul G. Shekelle, MD, PhD; Glenn S. Takata, MD, MS
[+] Author Affiliations

Author Affiliations: Department of Pediatrics, Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California (Dr Coker); RAND, Santa Monica, California (Dr Coker); Division of Biostatistics and Outcomes Assessment, Los Angeles County–USC Medical Center, Los Angeles (Dr Chan); USC Keck School of Medicine, Los Angeles (Drs Chan, Limbos, and Takata); Southern California Evidence-based Practice Center, RAND Health, Santa Monica, California (Drs Newberry and Shekelle and Ms Suttorp); West Los Angeles VA Medical Center, Los Angeles (Dr Shekelle); and Division of General Pediatrics, Childrens Hospital Los Angeles, Los Angeles (Dr Takata).


JAMA. 2010;304(19):2161-2169. doi:10.1001/jama.2010.1651.
Text Size: A A A
Published online

Context Acute otitis media (AOM) is the most common condition for which antibiotics are prescribed for US children; however, wide variation exists in diagnosis and treatment.

Objectives To perform a systematic review on AOM diagnosis, treatment, and the association of heptavalent pneumococcal conjugate vaccine (PCV7) use with AOM microbiology.

Data Sources PubMed, Cochrane Databases, and Web of Science, searched to identify articles published from January 1999 through July 2010.

Study Selection Diagnostic studies with a criterion standard, observational studies and randomized controlled trials comparing AOM microbiology with and without PCV7, and randomized controlled trials assessing antibiotic treatment.

Data Extraction Independent article review and study quality assessment by 2 investigators with consensus resolution of discrepancies.

Results Of 8945 citations screened, 135 were included. Meta-analysis was performed for comparisons with 3 or more trials. Few studies examined diagnosis; otoscopic findings of tympanic membrane bulging (positive likelihood ratio, 51 [95% confidence interval {CI}, 36-73]) and redness (positive likelihood ratio, 8.4 [95% CI, 7-11]) were associated with accurate diagnosis. In the few available studies, prevalence of Streptococcus pneumoniae decreased (eg, 33%-48% vs 23%-31% of AOM isolates), while that of Haemophilus influenzae increased (41%-43% vs 56%-57%) pre- vs post-PCV7. Short-term clinical success was higher for immediate use of ampicillin or amoxicillin vs placebo (73% vs 60%; pooled rate difference, 12% [95% CI, 5%-18%]; number needed to treat, 9 [95% CI, 6-20]), while increasing the rate of rash or diarrhea by 3% to 5%. Two of 4 studies showed greater clinical success for immediate vs delayed antibiotics (95% vs 80%; rate difference, 15% [95% CI, 6%-24%] and 86% vs 70%; rate difference, 16% [95% CI, 6%-26%]). Data are absent on long-term effects on antimicrobial resistance. Meta-analyses in general showed no significant differences in antibiotic comparative effectiveness.

Conclusions Otoscopic findings are critical to accurate AOM diagnosis. AOM microbiology has changed with use of PCV7. Antibiotics are modestly more effective than no treatment but cause adverse effects in 4% to 10% of children. Most antibiotics have comparable clinical success.

Figures in this Article

Quiz Ref IDAcute otitis media (AOM) is the most common childhood infection for which antibiotics are prescribed in the United States.13 A study using 2006 Medical Expenditure Panel Survey data demonstrated an average expenditure of $350 per child with AOM, totaling $2.8 billion.4 Timely and accurate diagnosis and appropriate management of AOM may have significant consequences for ambulatory health care utilization and expenditures.

Multiple systematic reviews on AOM diagnosis and management have been conducted,510 including our 2001 study,11 which was the basis for the 2004 American Academy of Pediatrics and American Academy of Family Physicians joint practice guidelines.12 Since then, new trials have been published, the heptavalent pneumococcal conjugate vaccine (PCV7) has become widely used, and clinician practice has changed regarding antibiotic choice for AOM.13

In light of these additional studies and practice changes, we conducted a systematic review to support the new AOM practice guidelines (currently in preparation) from the American Academy of Pediatrics. We report on the evidence for (1) the precision and accuracy of AOM diagnosis, (2) the association of PCV7 use with changes in AOM microbial epidemiology, (3) the decision about whether to treat with antibiotics, and (4) the comparative effectiveness of different antibiotics for uncomplicated AOM in average-risk children and associated antibiotic-related adverse events.

Literature Search and Study Selection

We searched PubMed, the Cochrane Controlled Clinical Trials Register Database, the Cochrane Database of Reviews of Effectiveness, and the Web of Science for articles published January 1999 through July 2010 on AOM diagnosis, treatment outcomes, and association of PCV7 use with changes in AOM microbiology using Medical Subject Headings terms (eg, otitis media, vaccines), key words (eg, diagnostic, microbiology, therapy), and individual antibiotic terms. This search supplemented a previous January 1966 through March 1999 search with additional key words for PCV7 and newer antibiotics.11 We performed reference mining of relevant systematic reviews.

We included articles in any language that studied children aged 4 weeks to 18 years. We excluded studies on children with immunodeficiencies and craniofacial anomalies. Systematic reviews, randomized controlled trials (RCTs), controlled clinical trials, and observational studies were included in the initial search; case reports, clinical overviews, editorials, and practice guidelines were excluded.

Observational studies were considered for the PCV7 and diagnostic questions but excluded for the treatment question. For the PCV7 question, only articles that assessed AOM microbiology (using middle ear fluid) both before and after PCV7 implementation were included. For the diagnostic question, we considered studies of children that performed independent comparisons of signs or symptoms with a clear criterion standard; studies using clinicians in training were excluded. For the antibiotic comparative effectiveness question, only studies that examined clinical improvement as an outcome (not just microbiologic findings) were included. The search strategy and inclusion/exclusion criteria are detailed elsewhere.14

Data Abstraction

Two investigators (T.R.C., M.A.L.) independently reviewed titles and abstracts for potentially relevant articles. They then independently abstracted data from the full-text articles using structured review forms that included inclusion/exclusion criteria, outcome measures, and study quality. Disagreements were resolved by consensus; the principal investigators (P.G.S., G.S.T.) resolved remaining disagreements. The study biostatistician abstracted data (verified by a clinician investigator) for pooled analyses. One investigator independently abstracted treatment-related adverse event data.

Quality Assessment

We used the Jadad criteria to assess RCT quality,15 AMSTAR16 to assess systematic review quality, and QUADAS17 to assess diagnostic study quality.

Data Synthesis

For diagnostic studies, we report summary data, including sensitivities and specificities, when available. The number of studies was insufficient to allow pooling of data across studies. Furthermore, the criterion standards for the diagnostic studies varied widely.

For studies examining the association between PCV7 use and changes in AOM microbial epidemiology, we report summary data; the studies were too few in number and lacked enough consistency across study design and population for pooled analysis.

For treatment studies, an adequate number of articles was identified for pooled analyses of some comparisons. Comparisons were grouped by individual antibiotics rather than by antibiotic class to maximize the clinical relevance of our findings. The only a priori exception was to group ampicillin with amoxicillin because of similarity. When 3 or more articles examined the same comparison, we used the DerSimonian and Laird random-effects model to pool rate differences across studies.18 Sensitivity analysis was performed for pooled significant findings.

For pooled estimates, we report the I2 statistic and P value for the χ2 test of heterogeneity, which tests the null hypothesis that individual study results are homogeneous.19,20I2 values near 100% represent high degrees of heterogeneity. For assessment of publication bias in our pooled analyses, we report the Egger asymmetry test.

We used Stata version 10.0 to perform the meta-analyses.21 The study received a waiver of institutional review board review from the RAND Human Subjects Protection Committee.

The literature searches and reference mining yielded 8945 titles. After removal of duplicates and clearly irrelevant titles, 738 went for further review. After 2 rounds of screening, 55 articles were accepted and combined with 80 articles identified from the 2001 systematic review.11 These included 4 articles (3 research articles plus 1 systematic review) on diagnosis, 6 on PCV7-microbiology, and 125 on antibiotic treatment (Figure 1).

Place holder to copy figure label and caption
Figure 1. Article Selection
Graphic Jump Location

AOM indicates acute otitis media; PCV7, heptavalent pneumococcal conjugate vaccine.
aThe brief screener was a 1-page screener used to screen abstracts to determine if the article contained original research data, met basic inclusion criteria, and addressed research questions.
bExtended screeners included more detailed information, including study design, sample size and identity, treatment protocol, types of outcomes reported and by whom, potential influencing factors, and study quality.
cRothman et al.5
dTakata et al.11

AOM Diagnosis

In clinical practice, 3 criteria are used to diagnose AOM: (1) acute symptoms of infection, (2) evidence of middle ear inflammation, and (3) presence of middle ear effusion (MEE).12 Published research focuses on what constitutes acute symptoms of infection and what physical findings are associated with middle ear inflammation or effusion. A challenge with interpreting this research is the lack of a consistent gold standard, which varied from otolaryngologist-made diagnosis to tympanocentesis.

We identified 1 systematic review5 and 3 additional studies2224 that addressed the question of diagnostic accuracy and precision in identifying any or all of the 3 criteria. Detailed data on these studies are available in our evidence report14; findings suggest that certain otoscopic signs are strongly associated with AOM, while data on the importance of symptoms as a predictor of AOM are less convincing.

Symptoms. A 2003 review by Rothman et al5 found that ear pain (sensitivities: 54%, 60%, 100%; specificities: 82% and 92%; positive likelihood ratio [LR], 3.0 [95% confidence interval {CI}, 2.1 to 4.3]; positive LR, 7.3 [95% CI, 4.4 to 12.1]) and ear rubbing (sensitivity: 42%; specificity: 87%; positive LR, 3.3 [95% CI, 2.1 to 5.1]) were modestly associated with AOM diagnosis. The review by Rothman et al included 4 studies examining specific symptoms among 965 total participants.2528 In 2 of the studies, participants were recruited from otolaryngology practices and may not be representative of the general population of children with AOM. A more recent single study found that among 469 children aged 6 to 36 months presenting to primary care offices with parent-suspected AOM, AOM diagnosis was not associated with occurrence, duration, or severity of parent-reported symptoms (eg, ear rubbing, ear pain, fever).24

Quiz Ref IDOtoscopic Signs. One study29 examined in the review by Rothman et al assessed the association of otoscopic findings of middle ear inflammation (redness: positive LR, 8.4 [95% CI, 7 to 11]) and effusion (cloudy: positive LR, 34 [95% CI, 28 to 42]; bulging: positive LR, 51 [95% CI, 36 to 73]; immobile: positive LR, 31 [95% CI, 26 to 37]) with AOM (determined by clinical symptoms and the presence of MEE on tympanocentesis).5

A study published subsequently to the review by Rothman et al examined the accuracy of tympanometric (evaluation of middle ear function by measurement of acoustic impedence) and otoscopic findings compared with tympanocentesis as the criterion standard to determine the presence of MEE. Among children with MEE on tympanocentesis, 97% had type B (abnormal) tympanometry results, and 100% had otoscopic examination findings consistent with AOM. These results may overestimate the accuracy of tympanometry, because the investigators performing otoscopy were not blinded to the tympanometry results, and the criterion standard of tympanocentesis was performed only when otoscopic or tympanometric findings suggested MEE.22

In another study subsequent to the review by Rothman et al, 22% of AOM cases diagnosed by a general practitioner were concurrently diagnosed by an otolaryngologist as otitis media with effusion, viral otitis, or a normal tympanic membrane.23

PCV7 and AOM Microbial Epidemiology

Six studies examined the association between PCV7 use and changes in AOM microbial epidemiology (Table). These studies fit into 2 categories: observational studies of AOM isolates both before and after the 2000 licensure of PCV7 and PCV7 efficacy RCTs examining AOM-related organisms.

Table Graphic Jump LocationTable. Studies of the Effects of Heptavalent Pneumococcal Conjugate Vaccine on Microbial Epidemiology of Acute Otitis Media

Most studies found that Haemophilus influenzae became more prevalent as an AOM isolate and that Streptococcus pneumoniae became less prevalent although it remained important.30,31,33 In an observational study of children with persistent AOM or AOM with treatment failure, the proportion of S pneumoniae MEE isolates decreased (from 44% in 1998-2000 to 31% in 2001-2003, P = .02), while the proportion of H influenzae isolates increased (from 43% in 1998-2000 to 57% in 2001-2003, P = .01).30 Another study found an increase (as a proportion of all S pneumoniae isolates) in nonvaccine serotype S pneumoniae and a decrease in vaccine serotype S pneumoniae (non-PCV7 S pneumoniae: from 12% in 1999 to 32% in 2002, P < .01).32 In a vaccine-efficacy RCT, investigators found a greater proportion of S pneumoniae isolates in the control group (33%) than in the PCV7 group (23%) (P < .001).34 It is important to note that study findings did not always reach statistical significance, and most studies focused on patients with severe or persistent AOM.

Antibiotics for Uncomplicated AOM

One hundred twenty-five articles compared the effectiveness of antibiotic treatment options in uncomplicated AOM. Older articles that examined antibiotics no longer typically used for AOM are not discussed here but are included in the evidence reports.14,36

Benefits of Antibiotic Treatment

Evidence about the benefits of treating with antibiotics comes from 2 types of studies: placebo-controlled studies of immediate use of antibiotics and studies comparing immediate use of antibiotics with a strategy of observation with possible delayed treatment (“wait-and-see” or “prescription-to-hold”).

Ampicillin or Amoxicillin vs Placebo

We identified 8 studies that compared ampicillin or amoxicillin with placebo. One did not report clinical success (only pain resolution) and was not included in the pooled analysis.37

Quiz Ref IDIn pooled analysis of the remaining 7 RCTs, the random-effects pooled rate difference for success by day 14 was estimated at 12% (95% CI, 5% to 18%), with a 73% success rate for ampicillin/amoxicillin and a 60% success rate for placebo. The number needed to treat (NNT) for clinical success was 9 (95% CI, 6 to 20) (eTable 1 and Figure 2). The more recent, higher-quality studies reported smaller benefits. The I2 statistic was 69% (P = .04 by χ2 test of heterogeneity), indicating the presence of unexplained heterogeneity, which could be attributable to differences in the populations studied, research methods used, or both. The Egger test did not suggest publication bias (P = .77).

Place holder to copy figure label and caption
Figure 2. Treatment Success by Day 14 for Ampicillin/Amoxicillin vs Placebo
Graphic Jump Location

Sizes of data markers are proportional to the sample size of each study in the analysis. CI indicates confidence interval.

In sensitivity analyses, we excluded an outlier38 because its 95% CI favored placebo far more strongly than any other individual study. The pooled analysis with the remaining 6 articles yielded rates of 70% vs 54% (pooled rate difference, 13% [95% CI, 8% to 19%]), with 7 children (95% CI, 5 to 12) needing treatment with ampicillin/amoxicillin to gain a case of clinical success (I2 = 62%, P = .09; P = .18 by Egger test).3944 When we pooled the 4 studies with a quality score of 3 or more (of 5), excluding the outlier, the rates were 76% vs 67% (pooled rate difference, 10% [95% CI, 6% to 14%]), and the NNT was 10 (95% CI, 7 to 18), without evidence of heterogeneity (I2 = 0.0%, P = .48) or publication bias (P = .26).41,43,44

Other Antibiotics vs Placebo

We identified 5 studies that compared other antibiotics with placebo (eTable 1), but they are not included in pooled analysis because we examined the overall benefit of antibiotics more commonly prescribed for AOM (ie, amoxicillin) over placebo.

Immediate vs Delayed Antibiotics

We identified 4 studies of delayed treatment approaches; 2 reported higher rates of clinical success with immediate compared with delayed use of antibiotics,45,46 and 2 found no difference.47,48 One article reported rates of 95% vs 80% (rate difference, 15% [95% CI, 6% to 24%]; NNT, 7 [95% CI, 4 to 17]) favoring amoxicillin over the wait-and-see approach for parent-perceived success at day 12,49 whereas the other reported rates of 86% vs 70% (rate difference, 16% [95% CI, 6% to 26%]; NNT, 6 [95% CI, 4 to 17]), also favoring amoxicillin over the prescription-to-hold approach for parent-perceived clinical success at day 3.45 Thirty-four percent46 and 24%46 of participants in the delayed antibiotic groups in these studies received delayed antibiotics, respectively.

Short-term Harms of Antibiotic Treatment

The risk of harms from antibiotic treatment for AOM has been less well studied than the benefits. Four of the 7 placebo-controlled studies reported on harms. One reported the counterintuitive, although not statistically significant, result of more cases of rash and diarrhea in placebo-treated patients than in amoxicillin-treated patients.44 Pooled analysis of the other 3 trials39,41,43 yielded rates of 13% vs 8% for diarrhea (pooled rate difference, 5% [95% CI, 0% to 10%]; I2 = 23%; P = .30), while 2 individual studies had a rate difference of 4% (4% vs 0%) and 3% (8% vs 5%) for rash39,41; these differences did not reach statistical significance. These point estimates are compatible with published estimates of the rate of rash (3%-10%) and diarrhea (5%-10%).5053 In the studies by Little et al45 and Spiro et al,47 the rate of diarrhea was higher for the antibiotic group than for the prescription-to-hold group (19% vs 9%; rate difference, 10% [95% CI, 2% to 18%] and 23% vs 8%; rate difference, 14% [95% CI, 6% to 22%] for the 2 studies, respectively), with a number needed to harm (NNH) of 10 (95% CI, 6 to 50) and 7 (95% CI, 5 to 17), respectively.45,47

McCormick et al49 reported no difference in the rate of antibiotic-related adverse events, and Neumark et al48 did not examine adverse events. In RCTs comparing amoxicillin with other antibiotics, the proportion of amoxicillin-treated children reporting rash ranged from 2% to 11% and the proportion reporting diarrhea ranged from 3% to 16%.5460

Long-term Harms of Antibiotic Treatment

None of the studies evaluated the rates of longer-term adverse effects of immediate antibiotic treatment, including antibiotic resistance.

Antibiotic Comparative Effectiveness

eTable 2 describes selected antibiotic comparative effectiveness studies and pooled analyses for comparisons examining 3 or more studies. The Egger test was not suggestive of publication bias for any of the pooled analyses.

The success rate differences were statistically nonsignificant in the pooled analyses comparing ampicillin/amoxicillin vs ceftriaxone (4 trials, I2 = 50.7%), ampicillin/amoxicillin vs cefixime (4 trials, I2 = 22.9%), ampicillin/amoxicillin vs cefaclor (4 trials, I2 = 13.0%), amoxicillin-clavulanate vs ceftriaxone (5 trials, I2 = 22.9%), cefaclor vs azithromycin (3 trials, I2 = 0%), and amoxicillin-clavulanate vs 5 days of azithromycin (5 trials, I2 = 62.2%) and vs 3 or fewer days of azithromycin (7 trials, I2 = 84.1%).

Statistically significant differences between treatment regimens were found in a few individual studies. Amoxicillin-clavulanate was superior to cefaclor (97% vs 84%; rate difference, 13% [95% CI, 5% to 21%])61; 10 days of amoxicillin-clavulanate was superior to 5 days of azithromycin (86% vs 70%; rate difference, 16% [95% CI, 2% to 30%])62; 5 days of amoxicillin-clavulanate was not as effective as 7 to 10 days (77% vs 88%; rate difference, −11% [95% CI, −20% to −3%] in the study by Cohen et al63 and 71% vs 87%; rate difference, −16% [95% CI, −24% to −8%] in the study by Hoberman et al64); and 5 days of ceftibuten was not as effective as 10 days of ceftibuten (78% vs 98%; rate difference, −20% [95% CI, −28% to −12% ]).65

Antibiotic-Related Adverse Events

In the pooled comparisons, use of ampicillin/amoxicillin resulted in a lower rate of diarrhea than cefixime (14% vs 21%; rate difference, −8% [95% CI, −13% to −4%]; NNH, 12 [95% CI, 8 to 25]; I2 = 0%), and use of amoxicillin-clavulanate resulted in a higher rate of diarrhea than 1 dose of ceftriaxone (20% vs 9%; rate difference, 11% [95% CI, 7% to 16%]; NNH, 9 [95% CI, 6 to 15]; I2 = 10.8%) and higher rates of any adverse event compared with 5 days of azithromycin (26% vs 9%; rate difference, 16% [95% CI, 7% to 25%]; NNH, 6 [95% CI, 4 to 14]; I2 = 81.9%).

We identified several important findings for AOM diagnosis, microbiology, and antibiotic management.

Acute otitis media is a clinical diagnosis with 3 components: acute signs of infection, evidence of middle ear inflammation, and effusion.12 Evidence suggests that certain otoscopic findings (ie, a red and immobile or bulging tympanic membrane) predict AOM, but the accuracy or precision of a clinical diagnosis has not been determined. A major limitation to the evidence regarding diagnosis is the lack of a gold standard. The diagnostic tools studied (eg, otoscopy) are often part of the only available gold standard—a clinical diagnosis. Perhaps the most important way to improve diagnosis is to increase clinicians' ability to recognize and rely on key otoscopic findings.

Since the introduction of PCV7, there have been significant shifts in AOM microbiology, with S pneumoniae becoming less prevalent and H influenzae becoming more prevalent. A recent study of a single pediatric practice found evidence suggesting that this balance may be shifting again because of an increase in the proportion of AOM with nonvaccine S pneumoniae serotypes.66 These data and the introduction of PCV13 support the need for ongoing surveillance of AOM isolates.

Immediate ampicillin/amoxicillin treatment has a modest benefit compared with placebo or delayed antibiotics but also may be associated with more diarrhea and rash. Quiz Ref IDOf 100 average-risk children with AOM, approximately 80 would likely get better within about 3 days without antibiotics.67 If all were treated with immediate ampicillin/amoxicillin, an additional 12 would likely improve, but 3 to 10 children would develop rash and 5 to 10 would develop diarrhea. Clinicians need to weigh these risks (including possible long-term effects on antibiotic resistance) and benefits before prescribing immediate antibiotics for uncomplicated AOM.

Most antibiotics used to treat uncomplicated AOM in children at normal risk have similar rates of clinical success; we found no evidence of the superiority of any other antibiotic over amoxicillin.

Quiz Ref IDIn most cases of uncomplicated AOM when amoxicillin is appropriate (eg, excluding children with penicillin allergy and those who previously did not improve after a course of amoxicillin), there is no evidence for first-line use of higher-cost antibiotics (eg, cefdinir, cefixime). For a 20-kg child with AOM, a 7-day course of cefdinir costs approximately $96, compared with $34 for an equivalent course of amoxicillin (pricing information available at http://www.drugstore.com). In an analysis of data from the National Ambulatory Medical Care Survey, among visits for AOM (visits for a new problem without additional diagnoses requiring antibiotic therapy), amoxicillin was prescribed in 49%, amoxicillin-clavulanate in 16%, cefdinir in 14%, and other cephalosporins in 6%.13 If just half of the 14% of the estimated 8 million children who visit a physician for AOM annually4 were to receive amoxicillin instead of cefdinir (assuming the other half were appropriately prescribed cefdinir because of a non–type-1 penicillin allergy), the estimated annual savings would exceed $34 million. This estimate does not account for potential additional savings from adopting a less aggressive approach to antibiotic prescribing that might avoid a certain number of prescriptions altogether.

This review has several limitations that must be considered. First, article screening and data abstraction were not blinded, which may potentially introduce bias. However, there is evidence that blinding does not alter the results of meta-analyses.68 Second, we may not have identified some relevant evidence. For example, we did not search EMBASE or seek unpublished data. We used statistical tools to detect publication bias but found no evidence of it in our pooled analyses. Additionally, our findings on diagnosis and microbiology are greatly limited by the small number of studies; thus, caution should be used in interpreting our findings for these topics. To account for variation in study quality, we performed sensitivity analyses that pooled only high-quality studies. Third, the studies varied widely in their definitions of clinical success and in AOM diagnostic criteria. Some studies that did not use all 3 AOM diagnostic criteria may have included participants without AOM but with otitis media with effusion or no middle-ear abnormality at all.69,70 Lastly, our pooled analyses included studies completed before and after the licensing of PCV7. It is not clear how the changing microbiology of AOM may have influenced study findings; the heterogeneity of AOM over the past 20 years might favor an analysis that does not include pooling data from studies before and after 2000.69

One remaining question is what new evidence about antibiotic comparative effectiveness is needed. It is not enough to show statistical significance or lack thereof; the clinical importance of any difference must also be considered. This requires knowing the minimal clinically important difference (MCID) for treatment of AOM. Although there currently is no agreed-on value for the MCID, assuming an MCID of 5% (representing a “small” effect size, according to Cohen's classification71) means that when existing evidence falls entirely within or outside of this MCID, equivalence or significance can be concluded; when it does not, it can be concluded that more information is needed. Using this definition, we can conclude equivalence for 2 of the 8 pooled analyses in eTable 2 and that effects are inconclusive for the remaining 6. The MCID has important implications for our conclusions; for example, in contrast to a previous systematic review,7 we are unable to make definitive conclusions regarding the equivalency of short- vs long-term regimens analyzed by antibiotic when considering an MCID of 5%, except for 7 to 10 days of cefaclor vs 3 days of azithromycin.

To account for both statistical and clinical significance, sample sizes for AOM comparative effectiveness studies need to be large. Because approximately 80% of AOM cases resolve spontaneously,67 most RCTs will be able to test superiority of different antibiotics with only the remaining 20%. If the success rate is 88% for the treatment group and 80% for the control group, a sample size of 1150 per group would provide a 95% CI of the difference of 5% to 11%, which is outside the ±5% MCID; this sample size is much larger than that of any published AOM comparative effectiveness study.

We found evidence to guide the diagnosis and management of AOM in children; however, further research is needed that (1) examines clinicians' diagnostic accuracy and precision using the 3 AOM diagnostic criteria; (2) continues surveillance of AOM microbiology, especially in view of the newly approved PCV13; and (3) produces more high-quality studies on AOM management that include clear diagnostic criteria, a better-defined menu of clinical success measures that are universally applied, and more investigation into the comparative antibiotic-related adverse event rates that assesses whether any antibiotic regimen is superior to amoxicillin.

Corresponding Author: Tumaini R. Coker, MD, MBA, UCLA/RAND Center for Adolescent Health Promotion, David Geffen School of Medicine at UCLA, 10960 Wilshire Blvd, Ste 1550, Los Angeles, CA 90024 (tcoker@mednet.ucla.edu).

Author Contributions: Dr Shekelle had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Coker, Chan, Shekelle, Takata.

Acquisition of data: Coker, Chan, Newberry, Limbos, Takata.

Analysis and interpretation of data: Coker, Chan, Newberry, Limbos, Suttorp, Shekelle, Takata.

Drafting of the manuscript: Coker, Chan, Shekelle, Takata.

Critical revision of the manuscript for important intellectual content: Coker, Chan, Newberry, Limbos, Suttorp, Shekelle, Takata.

Statistical analysis: Chan, Suttorp.

Obtained funding: Shekelle.

Administrative, technical, or material support: Newberry.

Study supervision: Shekelle, Takata.

Financial Disclosures: Dr Takata reported owning 100 shares of Pfizer stock, which he sold at the start of the study. No other authors reported disclosures.

Funding/Support: This article is based on research conducted by the Southern California Evidence-based Practice Center (EPC) under contract with the Agency for Healthcare Research and Quality (AHRQ) (contract 290-2007-10056). This work was commissioned by AHRQ as an update to an earlier report and in support of the update of practice guidelines.

Role of the Sponsor: AHRQ had a role, through its sponsorship of the EPC program, in the general methods of EPC systematic reviews and in development of the key questions for each review. However, AHRQ had no role in the specific conduct of the review; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Disclaimer: The authors of this article are responsible for its contents. No statement in this article should be construed as an official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: Roberta Shanman, MLS (RAND Library), conducted the literature searches. Martha Timmer, MS (EPC, RAND Health, Santa Monica), provided scientific programming and data entry support for the evidence report prepared for AHRQ. Aneesa Motala, BA, and Breanne Johnsen, BS (EPC, RAND Health), contributed to the evidence report and the manuscript. As RAND employees, these individuals were compensated from the EPC contract for this study but none received additional compensation for their contributions.

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Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE,  et al.  Treatment of acute otitis media with a shortened course of antibiotics: a meta-analysis.  JAMA. 1998;279(21):1736-1742
PubMed   |  Link to Article
Rosenfeld RM, Vertrees JE, Carr J,  et al.  Clinical efficacy of antimicrobial drugs for acute otitis media: metaanalysis of 5400 children from thirty-three randomized trials.  J Pediatr. 1994;124(3):355-367
PubMed   |  Link to Article
Glasziou PP, Del Mar CB, Sanders SL, Hayem M. Antibiotics for acute otitis media in children.  Cochrane Database Syst Rev. 2004;(1):CD000219
PubMed
Takata GS, Chan LS, Shekelle PG, Morton SC, Mason W, Marcy SM. Evidence assessment of management of acute otitis media, I: the role of antibiotics in treatment of uncomplicated acute otitis media.  Pediatrics. 2001;108(2):239-247
PubMed   |  Link to Article
American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media.  Diagnosis and management of acute otitis media.  Pediatrics. 2004;113(5):1451-1465
PubMed   |  Link to Article
Coco A, Vernacchio L, Horst M, Anderson A. Management of acute otitis media after publication of the 2004 AAP and AAFP clinical practice guideline.  Pediatrics. 2010;125(2):214-220
PubMed   |  Link to Article
Southern California Evidence-based Practice Center.  Management of Acute Otitis Media, UpdateRockville, MD: Agency for Healthcare Research and Quality; 2010
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Shea BJ, Grimshaw JM, Wells GA,  et al.  Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews.  BMC Med Res Methodol. 2007;7:10
PubMed   |  Link to Article
Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews.  BMC Med Res Methodol. 2003;3:25
PubMed   |  Link to Article
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188
PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Laird NM, Mosteller F. Some statistical methods for combining experimental results.  Int J Technol Assess Health Care. 1990;6(1):5-30
PubMed   |  Link to Article
 Stata. Version 10 [computer program]. College Station, TX: StataCorp; 2007 
Saeed K, Coglianese CL, McCormick DP, Chonmaitree T. Otoscopic and tympanometric findings in acute otitis media yielding dry tap at tympanocentesis.  Pediatr Infect Dis J. 2004;23(11):1030-1034
PubMed   |  Link to Article
Legros JM, Hitoto H, Garnier F, Dagorne C, Dubin J, Fanello S. Reliability of the diagnosis of acute otitis media by general practitioners [in French].  Arch Pediatr. 2007;14(5):427-433
PubMed   |  Link to Article
Laine MK, Tähtinen PA, Ruuskanen O, Huovinen P, Ruohola A. Symptoms or symptom-based scores cannot predict acute otitis media at otitis-prone age.  Pediatrics. 2010;125(5):e1154-e1161
PubMed   |  Link to Article
Kontiokari T, Koivunen P, Niemelä M, Pokka T, Uhari M. Symptoms of acute otitis media.  Pediatr Infect Dis J. 1998;17(8):676-679
PubMed   |  Link to Article
Niemela M, Uhari M, Jounio-Ervasti K, Luotonen J, Alho OP, Vierimaa E. Lack of specific symptomatology in children with acute otitis media.  Pediatr Infect Dis J. 1994;13(9):765-768
PubMed   |  Link to Article
Heikkinen T, Ruuskanen O. Signs and symptoms predicting acute otitis media.  Arch Pediatr Adolesc Med. 1995;149(1):26-29
PubMed   |  Link to Article
Ingvarsson L. Acute otalgia in children—findings and diagnosis.  Acta Paediatr Scand. 1982;71(5):705-710
PubMed   |  Link to Article
Karma PH, Penttilä MA, Sipilä MM, Kataja MJ. Otoscopic diagnosis of middle ear effusion in acute and non-acute otitis media, I: the value of different otoscopic findings.  Int J Pediatr Otorhinolaryngol. 1989;17(1):37-49
PubMed   |  Link to Article
Casey JR, Pichichero ME. Changes in frequency and pathogens causing acute otitis media in 1995-2003.  Pediatr Infect Dis J. 2004;23(9):824-828
PubMed   |  Link to Article
Block SL, Hedrick J, Harrison CJ,  et al.  Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media.  Pediatr Infect Dis J. 2004;23(9):829-833
PubMed   |  Link to Article
McEllistrem MC, Adams JM, Patel K,  et al.  Acute otitis media due to penicillin-nonsusceptible Streptococcus pneumoniae before and after the introduction of the pneumococcal conjugate vaccine.  Clin Infect Dis. 2005;40(12):1738-1744
PubMed   |  Link to Article
Brook I, Gober AE. Bacteriology of spontaneously draining acute otitis media in children before and after the introduction of pneumococcal vaccination.  Pediatr Infect Dis J. 2009;28(7):640-642
PubMed   |  Link to Article
Eskola J, Kilpi T, Palmu A,  et al; Finnish Otitis Media Study Group.  Efficacy of a pneumococcal conjugate vaccine against acute otitis media.  N Engl J Med. 2001;344(6):403-409
PubMed   |  Link to Article
Veenhoven R, Bogaert D, Uiterwaal C,  et al.  Effect of conjugate pneumococcal vaccine followed by polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study.  Lancet. 2003;361(9376):2189-2195
PubMed   |  Link to Article
Marcy M, Takata G, Chan LS,  et al.  Management of Acute Otitis Media: Evidence Report/Technology Assessment No. 15Rockville, MD: Agency for Healthcare Research and Quality; 2001. Publication 01-E010
van Buchem FL, Dunk JH, van't Hof MA. Therapy of acute otitis media: myringotomy, antibiotics, or neither? a double-blind study in children.  Lancet. 1981;2(8252):883-887
PubMed   |  Link to Article
Halsted C, Lepow ML, Balassanian N, Emmerich J, Wolinsky E. Otitis media: microbiology and evaluation of therapy.  Ann N Y Acad Sci. 1967;145(2):372-378
PubMed   |  Link to Article
Laxdal OE, Merida J, Jones RH. Treatment of acute otitis media: a controlled study of 142 children.  Can Med Assoc J. 1970;102(3):263-268
PubMed
Howie VM, Ploussard JH. Efficacy of fixed combination antibiotics versus separate components in otitis media: effectiveness of erythromycin estrolate, triple sulfonamide, ampicillin, erythromycin estolate-triple sulfonamide, and placebo in 280 patients with acute otitis media under two and one-half years of age.  Clin Pediatr (Phila). 1972;11(4):205-214
PubMed   |  Link to Article
Burke P, Bain J, Robinson D, Dunleavey J. Acute red ear in children: controlled trial of non-antibiotic treatment in general practice.  BMJ. 1991;303(6802):558-562
PubMed   |  Link to Article
Kaleida PH, Casselbrant ML, Rockette HE,  et al.  Amoxicillin or myringotomy or both for acute otitis media: results of a randomized clinical trial.  Pediatrics. 1991;87(4):466-474
PubMed
Damoiseaux RA, van Balen FA, Hoes AW, Verheij TJ, de Melker RA. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years.  BMJ. 2000;320(7231):350-354
PubMed   |  Link to Article
Le Saux N, Gaboury I, Baird M,  et al.  A randomized, double-blind, placebo-controlled noninferiority trial of amoxicillin for clinically diagnosed acute otitis media in children 6 months to 5 years of age.  CMAJ. 2005;172(3):335-341
PubMed
Little P, Moore M, Warner G, Dunleavy J, Williamson I. Longer term outcomes from a randomised trial of prescribing strategies in otitis media.  Br J Gen Pract. 2006;56(524):176-182
PubMed
Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J. Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media.  BMJ. 2001;322(7282):336-342
PubMed   |  Link to Article
Spiro DM, Tay KY, Arnold DH, Dziura JD, Baker MD, Shapiro ED. Wait-and-see prescription for the treatment of acute otitis media: a randomized controlled trial.  JAMA. 2006;296(10):1235-1241
PubMed   |  Link to Article
Neumark T, Mölstad S, Rosén C,  et al.  Evaluation of phenoxymethylpenicillin treatment of acute otitis media in children aged 2-16.  Scand J Prim Health Care. 2007;25(3):166-171
PubMed   |  Link to Article
McCormick DP, Chonmaitree T, Pittman C,  et al.  Nonsevere acute otitis media: a clinical trial comparing outcomes of watchful waiting versus immediate antibiotic treatment.  Pediatrics. 2005;115(6):1455-1465
PubMed   |  Link to Article
Bartlett JG. Clinical practice: antibiotic-associated diarrhea.  N Engl J Med. 2002;346(5):334-339
PubMed   |  Link to Article
Adcock BB, Rodman DP. Ampicillin-specific rashes.  Arch Fam Med. 1996;5(5):301-304
PubMed   |  Link to Article
Geyman JP, Erickson S. The ampicillin rash as a diagnostic and management problem: case reports and literature review.  J Fam Pract. 1978;7(3):493-496
PubMed
deShazo RD, Kemp SF. Allergic reactions to drugs and biologic agents.  JAMA. 1997;278(22):1895-1906
PubMed   |  Link to Article
Berman S, Lauer BA. A controlled trial of cefaclor versus amoxicillin for treatment of acute otitis media in early infancy.  Pediatr Infect Dis. 1983;2(1):30-33
PubMed   |  Link to Article
Casellas JMJ Jr, Israele V, Marín M,  et al.  Amoxicillin-sulbactam versus amoxicillin-clavulanic acid for the treatment of non-recurrent-acute otitis media in Argentinean children.  Int J Pediatr Otorhinolaryngol. 2005;69(9):1225-1233
PubMed   |  Link to Article
McLinn SE. Cefaclor in treatment of otitis media and pharyngitis in children.  Am J Dis Child. 1980;134(6):560-563
PubMed
Leigh AP, Robinson D, Millar ED. A general practice comparative study of a new third-generation oral cephalosporin, cefixime, with amoxycillin in the treatment of acute paediatric otitis media.  Br J Clin Pract. 1989;43(4):140-143
PubMed
Owen MJ, Anwar R, Nguyen HK, Swank PR, Bannister ER, Howie VM. Efficacy of cefixime in the treatment of acute otitis media in children.  Am J Dis Child. 1993;147(1):81-86
PubMed
Kara CO, Ozuer MZ, Kilic I, Yalcin AN, Ergin H. Comparison of amoxicillin with second and third generation cephalosporins in the treatment of acute otitis media.  Infez Med. 1998;6(2):93-95
PubMed
Jacobson JA, Metcalf TJ, Parkin JL, Wenerstrom LG, Matsen JM. Evaluation of cefaclor and amoxycillin in the treatment of acute otitis media.  Postgrad Med J. 1979;55:(suppl 4)  39-41
PubMed   |  Link to Article
Subba Rao SD, Macias MP, Dillman CA, Ramos BD, Kierszenbaum JS, Soliman AE.Augmentin 415 Study Group.  A randomized, observer-blind trial of amoxicillin/clavulanate versus cefaclor in the treament of children with acute otitis media.  J Chemother. 1998;10(6):460-468
PubMed
Dagan R, Johnson CE, McLinn S,  et al.  Bacteriologic and clinical efficacy of amoxicillin/clavulanate vs. azithromycin in acute otitis media.  Pediatr Infect Dis J. 2000;19(2):95-104
PubMed   |  Link to Article
Cohen R, Levy C, Boucherat M, Langue J, de La Rocque F. A multicenter, randomized, double-blind trial of 5 versus 10 days of antibiotic therapy for acute otitis media in young children.  J Pediatr. 1998;133(5):634-639
PubMed   |  Link to Article
Hoberman A, Paradise JL, Burch DJ,  et al.  Equivalent efficacy and reduced occurrence of diarrhea from a new formulation of amoxicillin/clavulanate potassium (Augmentin) for treatment of acute otitis media in children.  Pediatr Infect Dis J. 1997;16(5):463-470
PubMed   |  Link to Article
Simon MW. Five- vs 10-day treatment of acute otitis media with ceftibuten in infants and children.  Adv Ther. 1997;14(6):312-317
Casey JR, Adlowitz DG, Pichichero ME. New patterns in the otopathogens causing acute otitis media six to eight years after introduction of pneumococcal conjugate vaccine.  Pediatr Infect Dis J. 2010;29(4):304-309
PubMed
Rosenfeld RM, Kay D. Natural history of untreated otitis media.  Laryngoscope. 2003;113(10):1645-1657
PubMed   |  Link to Article
Berlin JA.University of Pennsylvania Meta-analysis Blinding Study Group.  Does blinding of readers affect the results of meta-analyses?  Lancet. 1997;350(9072):185-186
PubMed   |  Link to Article
Pichichero ME, Casey JR. Diagnostic inaccuracy and subject exclusions render placebo and observational studies of acute otitis media inconclusive.  Pediatr Infect Dis J. 2008;27(11):958-962
PubMed   |  Link to Article
Chan LS, Takata GS, Shekelle P, Morton SC, Mason W, Marcy SM. Evidence assessment of management of acute otitis media, II: research gaps and priorities for future research.  Pediatrics. 2001;108(2):248-254
PubMed   |  Link to Article
Cohen J. Statistical Power Analysis for the Behavioral Sciences. Rev ed. New York, NY: Academic Press Inc; 1977:179-213

Figures

Place holder to copy figure label and caption
Figure 1. Article Selection
Graphic Jump Location

AOM indicates acute otitis media; PCV7, heptavalent pneumococcal conjugate vaccine.
aThe brief screener was a 1-page screener used to screen abstracts to determine if the article contained original research data, met basic inclusion criteria, and addressed research questions.
bExtended screeners included more detailed information, including study design, sample size and identity, treatment protocol, types of outcomes reported and by whom, potential influencing factors, and study quality.
cRothman et al.5
dTakata et al.11

Place holder to copy figure label and caption
Figure 2. Treatment Success by Day 14 for Ampicillin/Amoxicillin vs Placebo
Graphic Jump Location

Sizes of data markers are proportional to the sample size of each study in the analysis. CI indicates confidence interval.

Tables

Table Graphic Jump LocationTable. Studies of the Effects of Heptavalent Pneumococcal Conjugate Vaccine on Microbial Epidemiology of Acute Otitis Media

References

Daly KA, Brown JE, Lindgren BR, Meland MH, Le CT, Giebink GS. Epidemiology of otitis media onset by six months of age.  Pediatrics. 1999;103(6, pt 1):1158-1166
PubMed   |  Link to Article
McCaig LF, Besser RE, Hughes JM. Trends in antimicrobial prescribing rates for children and adolescents.  JAMA. 2002;287(23):3096-3102
PubMed   |  Link to Article
Teele DW, Klein JO, Rosner B. Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study.  J Infect Dis. 1989;160(1):83-94
PubMed   |  Link to Article
Soni A. Ear infections (otitis media) in children (0-17): use and expenditures, 2006. Statistical Brief No. 228. Agency for Healthcare Research and Quality Web site. http://www.meps.ahrq.gov/mepsweb/data_files/publications/st228/stat228.pdf. December 2008. Accessed September 20, 2010
Simel DL, Rothman R, Keitz S. Update: otitis media, child. In: Simel DL, Rennie D, eds. The Rational Clinical Examination: Evidence-Based Clinical Diagnosis. New York, NY: McGraw-Hill; 2009. http//www.jamaevidence.com/content/3484986. Accessed September 2, 2010
Spurling GK, Del Mar CB, Dooley L, Foxlee R. Delayed antibiotics for respiratory infections.  Cochrane Database Syst Rev. 2007;(3):CD004417
PubMed
Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE,  et al.  Short course antibiotics for acute otitis media.  Cochrane Database Syst Rev. 2000;(2):CD001095
PubMed
Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE,  et al.  Treatment of acute otitis media with a shortened course of antibiotics: a meta-analysis.  JAMA. 1998;279(21):1736-1742
PubMed   |  Link to Article
Rosenfeld RM, Vertrees JE, Carr J,  et al.  Clinical efficacy of antimicrobial drugs for acute otitis media: metaanalysis of 5400 children from thirty-three randomized trials.  J Pediatr. 1994;124(3):355-367
PubMed   |  Link to Article
Glasziou PP, Del Mar CB, Sanders SL, Hayem M. Antibiotics for acute otitis media in children.  Cochrane Database Syst Rev. 2004;(1):CD000219
PubMed
Takata GS, Chan LS, Shekelle PG, Morton SC, Mason W, Marcy SM. Evidence assessment of management of acute otitis media, I: the role of antibiotics in treatment of uncomplicated acute otitis media.  Pediatrics. 2001;108(2):239-247
PubMed   |  Link to Article
American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media.  Diagnosis and management of acute otitis media.  Pediatrics. 2004;113(5):1451-1465
PubMed   |  Link to Article
Coco A, Vernacchio L, Horst M, Anderson A. Management of acute otitis media after publication of the 2004 AAP and AAFP clinical practice guideline.  Pediatrics. 2010;125(2):214-220
PubMed   |  Link to Article
Southern California Evidence-based Practice Center.  Management of Acute Otitis Media, UpdateRockville, MD: Agency for Healthcare Research and Quality; 2010
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Shea BJ, Grimshaw JM, Wells GA,  et al.  Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews.  BMC Med Res Methodol. 2007;7:10
PubMed   |  Link to Article
Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews.  BMC Med Res Methodol. 2003;3:25
PubMed   |  Link to Article
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188
PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Laird NM, Mosteller F. Some statistical methods for combining experimental results.  Int J Technol Assess Health Care. 1990;6(1):5-30
PubMed   |  Link to Article
 Stata. Version 10 [computer program]. College Station, TX: StataCorp; 2007 
Saeed K, Coglianese CL, McCormick DP, Chonmaitree T. Otoscopic and tympanometric findings in acute otitis media yielding dry tap at tympanocentesis.  Pediatr Infect Dis J. 2004;23(11):1030-1034
PubMed   |  Link to Article
Legros JM, Hitoto H, Garnier F, Dagorne C, Dubin J, Fanello S. Reliability of the diagnosis of acute otitis media by general practitioners [in French].  Arch Pediatr. 2007;14(5):427-433
PubMed   |  Link to Article
Laine MK, Tähtinen PA, Ruuskanen O, Huovinen P, Ruohola A. Symptoms or symptom-based scores cannot predict acute otitis media at otitis-prone age.  Pediatrics. 2010;125(5):e1154-e1161
PubMed   |  Link to Article
Kontiokari T, Koivunen P, Niemelä M, Pokka T, Uhari M. Symptoms of acute otitis media.  Pediatr Infect Dis J. 1998;17(8):676-679
PubMed   |  Link to Article
Niemela M, Uhari M, Jounio-Ervasti K, Luotonen J, Alho OP, Vierimaa E. Lack of specific symptomatology in children with acute otitis media.  Pediatr Infect Dis J. 1994;13(9):765-768
PubMed   |  Link to Article
Heikkinen T, Ruuskanen O. Signs and symptoms predicting acute otitis media.  Arch Pediatr Adolesc Med. 1995;149(1):26-29
PubMed   |  Link to Article
Ingvarsson L. Acute otalgia in children—findings and diagnosis.  Acta Paediatr Scand. 1982;71(5):705-710
PubMed   |  Link to Article
Karma PH, Penttilä MA, Sipilä MM, Kataja MJ. Otoscopic diagnosis of middle ear effusion in acute and non-acute otitis media, I: the value of different otoscopic findings.  Int J Pediatr Otorhinolaryngol. 1989;17(1):37-49
PubMed   |  Link to Article
Casey JR, Pichichero ME. Changes in frequency and pathogens causing acute otitis media in 1995-2003.  Pediatr Infect Dis J. 2004;23(9):824-828
PubMed   |  Link to Article
Block SL, Hedrick J, Harrison CJ,  et al.  Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media.  Pediatr Infect Dis J. 2004;23(9):829-833
PubMed   |  Link to Article
McEllistrem MC, Adams JM, Patel K,  et al.  Acute otitis media due to penicillin-nonsusceptible Streptococcus pneumoniae before and after the introduction of the pneumococcal conjugate vaccine.  Clin Infect Dis. 2005;40(12):1738-1744
PubMed   |  Link to Article
Brook I, Gober AE. Bacteriology of spontaneously draining acute otitis media in children before and after the introduction of pneumococcal vaccination.  Pediatr Infect Dis J. 2009;28(7):640-642
PubMed   |  Link to Article
Eskola J, Kilpi T, Palmu A,  et al; Finnish Otitis Media Study Group.  Efficacy of a pneumococcal conjugate vaccine against acute otitis media.  N Engl J Med. 2001;344(6):403-409
PubMed   |  Link to Article
Veenhoven R, Bogaert D, Uiterwaal C,  et al.  Effect of conjugate pneumococcal vaccine followed by polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study.  Lancet. 2003;361(9376):2189-2195
PubMed   |  Link to Article
Marcy M, Takata G, Chan LS,  et al.  Management of Acute Otitis Media: Evidence Report/Technology Assessment No. 15Rockville, MD: Agency for Healthcare Research and Quality; 2001. Publication 01-E010
van Buchem FL, Dunk JH, van't Hof MA. Therapy of acute otitis media: myringotomy, antibiotics, or neither? a double-blind study in children.  Lancet. 1981;2(8252):883-887
PubMed   |  Link to Article
Halsted C, Lepow ML, Balassanian N, Emmerich J, Wolinsky E. Otitis media: microbiology and evaluation of therapy.  Ann N Y Acad Sci. 1967;145(2):372-378
PubMed   |  Link to Article
Laxdal OE, Merida J, Jones RH. Treatment of acute otitis media: a controlled study of 142 children.  Can Med Assoc J. 1970;102(3):263-268
PubMed
Howie VM, Ploussard JH. Efficacy of fixed combination antibiotics versus separate components in otitis media: effectiveness of erythromycin estrolate, triple sulfonamide, ampicillin, erythromycin estolate-triple sulfonamide, and placebo in 280 patients with acute otitis media under two and one-half years of age.  Clin Pediatr (Phila). 1972;11(4):205-214
PubMed   |  Link to Article
Burke P, Bain J, Robinson D, Dunleavey J. Acute red ear in children: controlled trial of non-antibiotic treatment in general practice.  BMJ. 1991;303(6802):558-562
PubMed   |  Link to Article
Kaleida PH, Casselbrant ML, Rockette HE,  et al.  Amoxicillin or myringotomy or both for acute otitis media: results of a randomized clinical trial.  Pediatrics. 1991;87(4):466-474
PubMed
Damoiseaux RA, van Balen FA, Hoes AW, Verheij TJ, de Melker RA. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years.  BMJ. 2000;320(7231):350-354
PubMed   |  Link to Article
Le Saux N, Gaboury I, Baird M,  et al.  A randomized, double-blind, placebo-controlled noninferiority trial of amoxicillin for clinically diagnosed acute otitis media in children 6 months to 5 years of age.  CMAJ. 2005;172(3):335-341
PubMed
Little P, Moore M, Warner G, Dunleavy J, Williamson I. Longer term outcomes from a randomised trial of prescribing strategies in otitis media.  Br J Gen Pract. 2006;56(524):176-182
PubMed
Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J. Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media.  BMJ. 2001;322(7282):336-342
PubMed   |  Link to Article
Spiro DM, Tay KY, Arnold DH, Dziura JD, Baker MD, Shapiro ED. Wait-and-see prescription for the treatment of acute otitis media: a randomized controlled trial.  JAMA. 2006;296(10):1235-1241
PubMed   |  Link to Article
Neumark T, Mölstad S, Rosén C,  et al.  Evaluation of phenoxymethylpenicillin treatment of acute otitis media in children aged 2-16.  Scand J Prim Health Care. 2007;25(3):166-171
PubMed   |  Link to Article
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