Management of Acute Otitis Media: Update

Evidence Report/Technology Assessment Number 198

Management of Acute Otitis Media: Update Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. HHSA 290 2007 10056 I Prepared by:

RAND Corporation, Santa Monica, CA 90407

Investigators Paul G. Shekelle, M.D., Ph.D.

Glenn Takata, M.D., M.S.

Sydne J. Newberry, Ph.D.

Tumaini Coker, M.D.

Mary Ann Limbos, M.D., M.P.H.

Linda S. Chan, Ph.D.

Martha M. Timmer, M.S.

Marika J. Suttorp, M.S.

Jason Carter, B.A.

Aneesa Motala, B.A.

Di Valentine, J.D.

Breanne Johnsen, B.A.

Roberta Shanman, M.L.S.

AHRQ Publication No. 11-E004 November 2010

This report is based on research conducted by the RAND Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-10056-I). The findings and conclusions in this document are those of the author(s), who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information in this report is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This report is intended as a reference and not as a substitute for clinical judgment. This report may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as 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.

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. Suggested Citation: Shekelle PG, Takata G, Newberry SJ, Coker T, Limbos M, Chan LS, Timmer M, Suttorp M, Carter J, Motala A, Valentine D, Johnsen B, Shanman R. Management of Acute Otitis Media: Update. Evidence Report/Technology Assessment No. 198. (Prepared by the Southern California Evidence-Based Practice Center under Contract No. 290 2007 10056 I). Rockville, MD: Agency for Healthcare Research and Quality. November 2010. Available at: http://www.ahrq.gov/downloads/pub/evidence/pdf/otitis/otitisup.pdf.

No investigators have any affiliations or financial involvement (e.g., employment, consultancies, honoraria, stock options, expert testimony, grants or patents received or pending, or royalties) that conflict with material presented in this report.

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Preface 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. This report was requested by the American Academy of Pediatrics (AAP). 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 comments on this evidence report. They may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850, or by e-mail to [email protected]. Carolyn M. Clancy, M.D. Director Agency for Healthcare Research and Quality

Jean Slutsky, P.A., M.S.P.H. Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality

Stephanie Chang, M.D., M.P.H. Director, EPC Program Agency for Healthcare Research and Quality

CAPT Ernestine Murray, R.N., B.S.N., M.A.S. EPC Program Task Order Officer Agency for Healthcare Research and Quality

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Acknowledgments We wish to acknowledge the invaluable guidance and expertise contributed to this project by the Technical Expert Panel members who are listed in Appendix F. We also thank CAPT Ernestine (Tina) Murray (AHRQ) for her patience, guidance, and input, and the Oregon Evidence-based Practice Center, Rose Relevo, for assistance with research on drug safety, and the administrative staff for assistance with preparation of the report.

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Structured Abstract Context: Acute Otitis Media (AOM), a viral or bacterial infection of the ear, is the most common childhood infection for which antibiotics are prescribed in the United States. In 2001, the Southern California Evidence-based Practice Center conducted a systematic review of the evidence comparing treatments of AOM. Objectives: This review updates the 2001 review findings on diagnosis and treatment of uncomplicated AOM, assesses the evidence for treatment of recurrent AOM, and assesses the impact of the heptavalent pneumococcal conjugate (PCV7) vaccine on the microbiology of AOM. Data Sources and Study Selection: Searches of PubMed and the Cochrane databases were conducted from January 1998 July 2010 using the same search strategies used for the 2001 report, with the addition of terms not considered in the 2001 review. The Web of Science was also searched for citations of the 2001 report and its peer-reviewed publications. Data Extraction: After review by two investigators against pre-determined inclusion/exclusion criteria, we included existing systematic reviews and randomized controlled clinical trials for assessment of treatment efficacy and safety. Pooled analysis was performed for comparisons with three or more trials. Results and Conclusions: Few studies were found that examined the accuracy and precision of the diagnosis of AOM. Since PCV7’s introduction, AOM microbiology has shifted significantly, with Streptococcus pneumoniae becoming less prevalent and Haemophilus influenzae (HF) increasing in importance. For uncomplicated AOM, pooled analysis indicates that nine children (95% CI: 6, 20) would need to be treated with ampicillin or amoxicillin rather than placebo to note a difference in the rate of clinical success. However, in four studies of delayed treatment approaches for uncomplicated AOM, two had higher rates of clinical success with immediate antibiotic therapy while two did not, and in three studies, a marked decrease in antibiotic utilization was noted. We are unable to draw definitive conclusions regarding the comparative effectiveness of different antibiotics for AOM in children with recurrent otitis media (ROM). For ROM, long-term antibiotic administration will decrease AOM episodes from 3 to 1.5 for every 12 months of treatment per otitis prone child during active treatment (95% CI: 1.2, 2.1); however, potential consequences of long-term treatment need to be considered. Data were insufficient to draw conclusions about comparative effectiveness of different treatment strategies in subgroups of children with uncomplicated AOM. Adverse events were generally more frequent for amoxicillin-clavulanate than for cefdinir, ceftriaxone, or azithromycin. Higher quality studies and improved reporting of study characteristics related to quality are needed to provide definitive conclusions for AOM and ROM treatment options.

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Contents Executive Summary .........................................................................................................................1

Evidence Report.............................................................................................................................19

Chapter 1. Introduction ..................................................................................................................21

Diagnostic Accuracy..............................................................................................................21

Management...........................................................................................................................21

Pneumococcal Conjugate Vaccine.........................................................................................22

Chapter 2. Methods.......................................................................................................................23

Original Proposed Key Questions.............................................................................................23

Technical Expert Panel .............................................................................................................24

Definitions of Acute Otitis Media.............................................................................................24

Literature Search .......................................................................................................................25

Article Review ..........................................................................................................................26

Study Inclusion ..................................................................................................................... 26

Screening............................................................................................................................... 26

Data Abstraction & Synethesis of Results ............................................................................... 27

Review and Assessment of Study Quality ............................................................................ 27

Data Abstraction ................................................................................................................... 27

Supplemental Analysis for Key Question III........................................................................ 27

Supplemental Analysis for Key Question IV........................................................................ 29

Supplemental Analysis for Key Question V......................................................................... 29

Supplemental Analysis for Key Question VI........................................................................ 29

Use of Observational Studies to Assess Comparative Effectiveness.................................... 30

Rating the Overall Quality of Scientific Evidence ............................................................... 30

Peer Review .................................................................................................................................. 33

Chapter 3. Results ..........................................................................................................................35

Key Question I. Diagnosis of AOM: What are the Operating Characteristics (Sensitivity,

Specificity, and Likelihood Ratios) of Clinical Symptoms and Otoscopic Findings (Such As

Bulging Tympanic Membrane) to Diagnose Uncomplicated AOM and to Distinguish It from

OME? .............................................................................................................................................35

Description of the Studies..................................................................................................... 35

Findings for Key Question I ................................................................................................. 35

Key Question II. What Has Been the Impact of the Pneumococcal Heptavalent Immunization (PCV7) on AOM Microbial Epidemiology (Including Acute Mastoiditis and Suppurative

Complications)?........................................................................................................................ 44

Description of the Studies..................................................................................................... 44

Findings for Key Question II ................................................................................................ 44

Findings According to Antibiotic History ............................................................................ 56

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Key Question III. What is the Comparative Effectiveness of Different Treatment Options for

Treating Uncomplicated Acute Otitis Media in Average Risk Children?................................ 56

Description of the Studies..................................................................................................... 56

Findings for Key Question III............................................................................................... 57

Ampicillin or Amoxicillin vs. Placebo ................................................................................. 79

Ampicillin or Amoxicillin vs. Ceftriaxone ........................................................................... 88

Amoxicillin-Clavulanate (7-10 days) vs. Ceftriaxone (single dose) .................................... 90

Amoxicillin-Clavulanate (7-10 days) vs. Azithromycin (≤5 days) ...................................... 93

Cefaclor vs. Azithromycin .................................................................................................... 99

Antibiotics vs. Wait-and-See/Prescription to Hold............................................................. 101

Other Meta-Analyses .......................................................................................................... 105

Summary ............................................................................................................................. 105

Key Question IV. What Is the Comparative Effectiveness of Different Management

Options for Recurrent Otitis Media (Uncomplicated) and Persistent Otitis Media or Relapse

of Acute Otitis Media? ........................................................................................................... 108

Description of the Studies................................................................................................... 108

Findings on Treatment of Acute Otitis Media in Children with Recurrent Otitis Media ... 119

Findings on Prevention of Acute Otitis Media in Children with Recurrent Otitis Media .. 123

Summary ............................................................................................................................. 128

Key Question V. Do Treatment Outcomes in Key Questions III and IV Differ by

Characteristics of the Condition (AOM), Patient, Environment, and/or Health Care

Delivery System? .................................................................................................................. 129

Age Factor in Uncomplicated Acute Otitis Media ............................................................. 130

Laterality Factor in Uncomplicated Acute Otitis Media..................................................... 151

Childcare Setting Factor in Uncomplicated Otitis Media................................................... 154

Other Factors Studied in Uncomplicated Otitis Media....................................................... 157

Effectiveness of Treatments in Recurrent Otitis Media, Stratified by Age, Laterality,

and Severity ........................................................................................................................ 160

Summary ............................................................................................................................. 164

Key Question VI. What Adverse Effects Have Been Observed for the Treatments Whose

Outcomes Are Addressed in Key Questions 3 and 4? .......................................................... 165

Description of the Studies................................................................................................... 165

Adverse Effects Observed In Treatment of Uncomplicated Acute Otitis Media ............... 165

Adverse Effects in Studies of Treatment of Acute Otitis Media in Children with

Recurrent Otitis Media or Persistent Acute Otitis Media ................................................... 175

Adverse Events Associated with Prevention of Acute Otitis Media in Children with

Recurrent Otitis Media........................................................................................................ 183

Summary ............................................................................................................................. 189

Chapter 4. Discussion ..................................................................................................................191

Limitations ..............................................................................................................................191

Publication Bias .................................................................................................................. 191

Study Quality ...................................................................................................................... 191

Conclusions........................................................................................................................... 191

Key Question I. Diagnosis of AOM ................................................................................... 191

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Key Question II. The impact of the Pneumococcal Heptavalent Immunization (PCV7)

on AOM Microbial Epidemiology...................................................................................... 192

Key Question III. Treatment of Uncomplicated AOM ....................................................... 197

Key Question IV. Prevention or Treatment of Acute Otitis Media in Children with

Recurrent Otitis Media........................................................................................................ 193

Key Question V................................................................................................................... 194

Key Question VI ................................................................................................................. 194

Future Research Suggestions .................................................................................................194

Key Question I: Diagnostic Criteria for AOM ................................................................... 195

Key Question II: Effects of the PCV7 Vaccine .................................................................. 195

Key Questions III-VI: Treatment Efficacy and Adverse Effects........................................ 195

References....................................................................................................................................199

List of Acronyms/Abbreviations..................................................................................................207

Figures Figure 1. Statistical Inference Using Confidence Interval (CI) and Minimal Clinically

Important Difference (MCID)........................................................................................................32

Figure 2. Shrinkage Plot for Ampicillin/Amoxicillin vs Placebo for Treatment Success .............80

Figure 3. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success

(Excluded Halsted 1967 Study) .....................................................................................................82

Figure 4. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success

(Included Studies with Quality Score 3, 4, or 5)............................................................................84

Figure 5. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success

(Included Studies with Quality Score 3, 4, or 5 (Excluded Halsted 1967 Study)..........................86

Figure 6. Shrinkage Plot for Ampicillin/Amoxicillin vs. Ceftriaxone for Treatment Success......90

Figure 7. Shrinkage Plot for Amoxicillin-clavulanate (7-10 days) vs. Ceftriaxone (single dose)

for Treatment Success....................................................................................................................93

Figure 8. Shrinkage Plot for Amoxicillin-Clavulanate (7-10 days) vs. Azithromycin (≤5 days)

for Treatment Success....................................................................................................................96

Figure 9. Shrinkage Plot for Amoxicillin-Clavulanate (7-10 days) vs, Azithromycin

(≤ 5 days) for Treatment Success (Excluded Pestalozza 1992 Study)...........................................97

Figure 10. Shrinkage Plot for Cefaclor vs. Azithromycin for Treatment Success ......................101

Figure 11. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success for

AGE ≤2 Years..............................................................................................................................146

Figure 12. Shrinkage Plot for Ampicillin/Amoxicillin vs. Placebo for Treatment Success for

AGE>2 Years...............................................................................................................................147

Figure 13. Shrinkage Plot for Amoxicillin-clavulanate (7-10 days) vs. Azithromycin

(2 Years..........................................................................................................................142

Table 27. Amoxicillin-Clavulanate (7-10 Days) vs. Azithromycin (2 Years by Treatment Option Based on Pooled Data.....................................................................................145

Table 30. Summary of Findings from Two Articles and One Previous Systematic Review

Reporting Effectiveness of Interventions in Uncomplicated Otitis Media Stratified by

Laterality ......................................................................................................................................152

Table 31. Summary of Findings from 2 Articles Reporting Effectiveness of Interventions in

Uncomplicated Otitis Media Stratified by Childcare Setting ......................................................156

Table 32. Summary of Findings from Articles Each Reporting Effectiveness of Interventions

in Uncomplicated Otitis Media Stratified by a Risk Factor.........................................................158

Table 33. Summary of Findings from Three Articles Reporting Effectiveness of Interventions

in Recurrent Otitis Media Stratified by Age, Laterality, and Severity. .......................................161

Table 34. Findings of Adverse Events by Treatment Option Comparisons for Uncomplicated

Otitis Media .................................................................................................................................166

Table 34a. Comparison of Rates of Adverse Events Between Drugs (Significant Differences

Only) ............................................................................................................................................173

Table 35. Comparison of Adverse Event Rates Between Treatment Options from Eight

Comparisions on Effectiveness of Treatment of Acute Otitis Media in Recurrent Otitis Media 177

Table 36. Findings of Adverse Events from Eight Articles on Effectiveness of Prevention of

Acute Otitis Media in Recurrent Otitis Media.............................................................................184

Table 37. Number of Randomized Controlled Trials in the Original Review by Marcy

(2001)13 and the Review Update by Number of AOM Diagnostic Criteria Used and by

Number of Jadad Study Quality Criteria Met ..............................................................................201

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Appendixes Appendix A: Scope, Definitions, and Search Strategies Appendix B: Sample Data Abstraction Forms Appendix C: Evidence Table Appendix D: List of Excluded Studies Appendix E: Peer Reviewers Appendix F: Technical Expert Panel Members and Meeting Summaries Appendix G: Summary Tables for Studies Included in Comparisons Appendix H: Conceptual Framework for the Report Appendix I: Summary of Systematic Reviews Included in Analyses Appendix J: Comparison of Original Research Studies Included in Systematic Reviews Appendixes and Evidence Tables for this report are provided electronically at http://www.ahrq.gov/downloads/pub/evidence/pdf/otitis/otitisup.pdf.

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Executive Summary Introduction 1

Acute Otitis Media (AOM) is a viral and/or bacterial infection of the middle ear and represents the most common childhood infection for which antibiotics are prescribed in the United States. Timely and accurate diagnosis and management of AOM can have significant individual and public health consequences. The 2001 AHRQ evidence report on the management of AOM analyzed the evidence on the initial management of uncomplicated AOM in children, focusing on the natural history of the disease and the use of antibiotics in management. Although the 2001 report provided valuable analysis of the literature on the management of uncomplicated AOM in children, it did not address issues related to diagnostic accuracy and precision, management of AOM in specific subgroups of children, or the impact of immunization with Heptavalent Pneumococcal Conjugate Vaccine (PCV7) on the microbiology of AOM, recommended for widespread use in 2000. Additionally, new trials of treatment continue to be published. The purpose of this current AHRQ evidence report is to examine and analyze the evidence on three broad areas of inquiry: 1) accuracy and consistency of the clinical diagnosis of AOM, 2) the impact of PCV7 on AOM microbial epidemiology, and 3) the comparative effectiveness of different treatment options for uncomplicated AOM in average risk children and in children with recurrent (defined as three or more episodes in six months or four or more episodes within 12 months) or persistent AOM.

Methods Key Questions The American Academy of Pediatrics, the nominating organization, proposed six key questions aimed at assessing the comparative efficacy of interventions to treat uncomplicated and recurrent AOM in terms of treatment success, the safety of such treatments, and the effect on children in specific subgroups. In conjunction with a technical expert panel we refined these questions: I. Diagnosis of AOM: What are the operating characteristics (sensitivity, specificity, and likelihood ratios) of clinical symptoms and otoscopic findings (such as bulging tympanic membrane), both individual and composite, to diagnose uncomplicated AOM and to distinguish it from otitis media with effusion (OME)?2 II. What has been the impact of the Pneumococcal Heptavalent Immunization (PCV7) on AOM microbial epidemiology (including acute mastoiditis and suppurative complications), with respect to both the organisms associated with AOM and the patterns of antimicrobial resistance? III. What is the comparative effectiveness of different treatment options for treating uncomplicated AOM in average risk children? 1

A diagnosis of AOM requires 1) a history of acute onset of signs and symptoms, 2) the presence of middle ear effusion (MEE), and 3) signs and symptoms of middle-ear inflammation. (Marcy, Takata, Shekelle, et al., 2001). 2 Otitis media with effusion (OME) is defined as fluid in the middle ear without signs or symptoms of acute infection. Distinguishing AOM from OME often poses a diagnostic challenge.

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IV. What is the comparative effectiveness of different management options for recurrent otitis media (uncomplicated) and persistent otitis media or relapse of AOM? V. Do treatment outcomes in Key Question3 (KQ3) and KQ4 differ by characteristics of the condition (AOM), patient, environment, and/or health care delivery system, including but not limited to the following: A. Laterality, i.e., unilateral vs. bilateral; B. Otorrhea or perforation; C. AOM severity, i.e., as defined as defined by the AAFP/AAP AOM Guideline (2004); D. Comorbidities, e.g., asthma; E. Age groups, e.g., 30 months) were more likely to have a certain diagnosis of AOM than children ≤ 12 months of age.19 Given the uncertainty associated with diagnosis, particularly in young children, it is important to continually assess the validity of the clinical signs and symptoms used to diagnose AOM.

Management Traditional management approaches have centered on the use of antimicrobials; a 2009 study found that prescription of broad-spectrum antibiotics for AOM increased from 34% of doctor visits in 1998 to 45% of visits in 2004.20 However, debate is increasing over their benefits. Concerns regarding increased antimicrobial resistance and uncertainty about the benefits of antibiotic treatments (e.g., AOM may be either bacterial or viral) have resulted in a number of clinical guidelines proposing more judicious use of antimicrobials.16, 21 The 2004 guidelines released by the American Academy of Pediatrics (AAP) and American Academy of Family Practice (AAFP) recommend antibiotics for all children under 6 months and an observation 21

approach for otherwise healthy children ages 6 months to less than 2 years who have BOTH an uncertain diagnosis and non-severe disease. Observation is also an option for otherwise healthy children 2 years of age or older with either non-severe disease or uncertain diagnosis.16 However, the benefits of a watchful waiting approach in young patients with a certain diagnosis of AOM are unclear. Amoxicillin is often recommended as the first-line antibiotic for children.16, 21 Although empiric therapy recommendations vary depending on the local antimicrobial resistance patterns, evidence of recent microbiologic shifts and changing resistance patterns associated with PCV7 warrant determining the effectiveness and safety of the current recommendations and evaluating additional antimicrobial agents and other management strategies. Recurrent otitis media (ROM), defined as three or more episodes in six months or four or more episodes within 12 months, occurs in 20% of children under six months of age.9 Antibiotic resistant Streptococcus pneumoniae (SP) is commonly associated with ROM and presents a significant therapeutic challenge.22, 23 The choice of antimicrobial is not always clear, and the role of prophylactic antibiotics remains uncertain.

Pneumococcal Conjugate Vaccine SP is a common bacterial isolate from the middle ear fluid of children with otitis media.24 In February 2000, a heptavalent pneumococcal polysaccharide protein conjugate vaccine (PCV7) was recommended for use in children aged 2-23 months and for children aged 24-59 months at increased risk for pneumococcal disease.25 These recommendations were expanded in 2007 to include all healthy, previously unvaccinated children 24-59 months of age. A question that needs to be addressed is whether PCV7 vaccination is associated with a microbiologic shift among pathogens commonly responsible for otitis media.

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Chapter 2. Methods Original Proposed Key Questions The American Academy of Pediatrics requested that AHRQ commission an update of the 2001 evidence review, Management of Acute Otitis Media. AHRQ provided an initial list of questions. 1. What is the validity of clinical symptoms and otoscopic findings such as a bulging tympanic membrane to diagnose AOM? Do these clinical findings aid physicians in distinguishing AOM from OME? 2. What organisms (bacterial and viral) are associated with otitis media since the introduction of PCV7? 3. What are the patterns of antimicrobial resistance since the introduction of PCV7? a. New infections b. Recurrent infections 4. What is the comparative effectiveness of different treatment options (defined below) for treating AOM in average risk children ages 6 mo, Bulging tympanic membrane [TM], Cloudy TM, Erythematous TM, Otorrhea, Pneumatic otoscopy/tympanometry (limited or absent mobility of TM), Otalgia within last 24 hours, Otoscopy (distinct TM erythema), Recurrent AOM, Persistent AOM Exclusion: Penicillin/beta-lactams, Any antibiotic, Any antibiotic during present illness, Concomitant/Concurrent infection needing antibiotic treatment, PE tubes/history of PE tubes, Major Systemic disease/ condition, medical problem, On other medication/treatment

Influencing Factors and Sample Size Influencing factors: Age Entering: N=1650 N=823 Amoxicillinclavulanate N=827 Levofloxacin Completing: N=1435 N=721 Amoxicillinclavulanate N=714 Levofloxacin Analyzed: N=1305 N=675 Amoxicillinclavulanate N=630 Levofloxacin

Outcomes Treatment failure; By Pneumatic otoscopy/tympanometry; Signs or symptoms of MEI; By symptoms (otalgia, ear fullness); By otoscopy (distinct TM erythema); Other symptoms: fever; Adverse effects of treatment

Findings Outcome: Clinical success (cure and improved) at 2-5 days Age Levofloxacin Amox-clav Diff (95%CI) 0.5-2-