CM E

Update: Acute Otitis Media

Nader Shaikh, MD, MPH; and Alejandro Hoberman, MD

CM E

EDUCATIONAL OBJECTIVES

1. Review the recent changes in the microbiology of acute otitis media. 2. Differentiate the physical exam ndings characteristic of acute otitis media (AOM) from those of otitis media with effusion (OME). 3. Discuss the evidence to support antimicrobial management of AOM in children. Nader Shaikh, MD, MPH; and Alejandro Hoberman, MD, are with the Division of General Academic Pediatrics, University of Pittsburgh School of Medicine, and Childrens Hospital of Pittsburgh. Address correspondence to: Nader Shaikh, MD, MPH, General Academic Pediatrics, Childrens Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 152132583; fax: 412-692-8516; e-mail: nader. shaikh@chp.edu. Dr. Shaikh and Dr. Hoberman have disclosed no relevant financial relationships. doi: 10.3928/00904481-20091222-03

cute otitis media (AOM) remains one of the most common clinical problems in childhood; 84% of all children will have experienced at least one episode of AOM by 3 years.1 Otitis media is a general term for middle ear inflammation and may be classified clinically as either AOM or otitis media with effusion (OME).2 OME may occur first (and predispose to) the development of AOM, may occur as the aftermath of an episode of AOM, or may occur as a consequence of eustachian tube dysfunction, which is most often attributable to viral upper respiratory tract infections.3 Accordingly, AOM and OME are segments of a disease continuum. PATHOPHYSIOLOGY The antecedent event in most cases of AOM is a viral upper respiratory tract infection, which causes inflammation of the mucosa of the upper respiratory tract, including the naso-

28 | www.PediatricSuperSite.com

PEDIATRIC ANNALS 39:1 | JANUARY 2010

3901Shaikh.indd 28

1/6/2010 3:06:17 PM

CM E
results in low-level resistance, whereas the other mechanism of resistance involves alterations in ribosomes and results in high-level resistance.9 The prevalence of drug-resistant S. pneumoniae (DRSP) and beta-lactamase-producing H. inuenzae is greatly inuenced by age, recent exposure to antibiotics, attendance at daycare, and pneumococcal immunization status.3 The prevalence is relatively high in children younger than 24 months of age, those who have recently received treatment with beta-lactam drugs, and those who are exposed to large numbers of other children (as are present in daycare or in large families).10 Although 7-valent pneumococcal (PCV7) vaccination initially was associated with a moderate decrease in the prevalence of S. pneumoniae and an increase in H. inuenzae cultured from middle ear aspirates,6,7 more recent studies suggest that this shift may have been temporary (with the proportion of H. inuenzae and S. pneumoniae now being about equal).8 Similarly, although there was an initial decrease in the vaccine serotypes (which included the majority of isolates of S. pneumoniae that were resistant to penicillin), there was rapid replacement of these serotypes with non-vaccine stains.11 Some of these emerging nonvaccine serotypes, especially 19A, are not only multidrug resistant but also have great potential to cause invasive disease. Currently, approximately 50% of nasopharyngeal isolates of S. pneumoniae are penicillin-resistant, and about 50% of H. inuenzae produce beta-lactamase.8 RISK FACTORS FOR OTITIS MEDIA The peak incidence of AOM is in the rst 2 years of life, particularly between 6 and 12 months. The increased susceptibility of infants may be explained, at least in part, by anatomic features (characteristics of the eustachian tube, such as short length, horizontal position, and high compliance) and immunologic fac-

Figure 1. Normal tympanic membrane.

pharynx and eustachian tube. Eustachian tube dysfunction impairs middle ear fluid drainage and establishes an environment that is conducive to bacterial growth.4 Bacteria are isolated from middle ear fluid in approximately 70% of children with bulging tympanic membranes (TM). Only rarely (about 6% of cases) do viral infections alone (in the absence of a bacterial superinfection) result in clinical features consistent with AOM.5 MICROBIOLOGY Streptococcus pneumoniae or nontypable Haemophilus inuenzae are recovered, in approximately equal proportions, from 90% of children with AOM.6-8 Other less frequently involved pathogens include Moraxella catarrhalis (5% to 10%), group A streptococci (2%), Staphylococcus aureus (1%), and gram-negative organisms, such as Pseudomonas aeruginosa (1%).

Development of bacterial resistance occurs by a variety of adaptive mechanisms and is an increasing clinical problem in children with AOM. Although some strains of H. inuenzae and most strains of M. catarrhalis are resistant to amoxicillin by virtue of their production of beta-lactamase, in most cases, such resistance can be overcome by using a combination of a beta-lactam antibiotic, with a beta-lactamase inhibitor (eg, amoxicillin/clavunalate), or by using beta-lactamase-stable antibiotics (eg, cefuroxime). In contrast, the primary mechanism of resistance among strains of S. pneumoniae involves alterations in penicillin-binding proteins. This mechanism of resistance can usually be overcome by achieving higher concentrations of antibiotic at the site of infection. Two mechanisms of resistance to macrolides have been identied among strains of S. pneumoniae. One mechanism involves an efux pump and

PEDIATRIC ANNALS 39:1 | JANUARY 2010

www.PediatricSuperSite.com | 29

3901Shaikh.indd 29

1/6/2010 3:06:18 PM

CM E
full, bulging), its color (gray, yellow, pink, amber, white, red, blue), its translucency (translucent, semiopaque, opaque), and its mobility (normal, increased, decreased, absent) in the assessment of middle ear status. The normal TM is translucent, pearly gray, and has a ground-glass appearance (see Figure 1, page 29). Specic landmarks can be visualized. They include the incudostapedial joint and the manubrium of the malleus. OME is diagnosed when there is evidence of middle ear effusion but no signs of acute inammation (see Figure 2). When middle ear uid is present, the TM is discolored, is opaque, and exhibits decreased mobility on pneumatic otoscopy. An amber discoloration is highly suggestive of OME. The presence of an air-uid level in a child with a neutral TM is consistent with a diagnosis of OME. In contrast, a diagnosis of AOM is justied when, in addition to evidence of middle ear effusion, there is marked redness or bulging of the TM (see Figure 3, page 31). Fever may or may not be present. In some children with AOM, bullae lled with purulent, serous, or bloody effusion may be seen. In other children with AOM, the TM exhibits a cobblestoned appearance. TREATMENT OF AOM The treatment of AOM remains controversial. Antibiotic use is associated with increased antibiotic resistance among the pathogens causing AOM. Thus, it is of paramount importance to have evidence-based guidelines to justify their use. Avoidance of inappropriate or excessive antibiotic use for treatment of children with OME (misdiagnosed as having AOM) or for treatment of non-specic upper respiratory tract symptoms is an important step in preventing antimicrobial resistance. To date, nine randomized trials have examined the efcacy of antibiotics compared with placebo in reducing the severity and duration of pain in children

Figure 2. A. Amber tympanic membrane. B. Neutral tympanic membrane with a visible air-uid level.

tors (limited response to antigens and lack of previous exposure to common bacterial and viral pathogens). Age at the rst episode of AOM is inversely associated with risk for recurrent episodes. Children who have Down syndrome or immunologic deciencies (congenital or acquired) have a high incidence of AOM, as do Native American, Alaskan, and Canadian Inuit children. Findings from twin and adoption studies suggest a strong genetic predisposition to otitis media.12 AOM is also a remarkably seasonal disease, occurring predominantly during the winter but also in the fall and spring. Low socioeconomic status and exposure to large numbers of other children (eg, in daycare) are also important risk factors for development of AOM.2 Seasonality, age, and daycare exposures probably relate most directly to the risk of acquisition of viral upper respiratory infections. DIAGNOSIS Accurate diagnosis of otitis media in infants and young children is often difcult. Symptoms frequently overlap with those of upper respiratory illness. Ear pain is the most specic symptom but often seems absent in children with AOM.13 The TM may be obscured by cerumen, and subtle changes in the TM may be difcult to discern. The pneumatic otoscope is the standard tool used in diagnosing otitis me-

dia. If the TM is initially obscured by cerumen, a blunt curette may be used to carefully remove the cerumen from the canal under direct visualization through

AOM is also a remarkably seasonal disease, occurring predominantly during the winter but also in the fall and spring.
the otoscope. Often any remaining bits can then be wiped away using a Farrell applicator, with its tip (triangular in cross-section) wrapped with a bit of dry or alcohol-moistened cotton to create a dry or wet mop. Alternatively, gentle suction or irrigation may be used. Young children should be restrained in the prone or supine position throughout the procedure. One adult, usually a parent, braces the childs body against the examining table. Another adult can restrain the patients head. One of the assistants must also hold the childs hands. The pneumatic otoscope should have a light source of sufcient brightness and an air-tight system that permits application of positive and negative pressure. Pneumatic otoscopy permits assessment of the contour of the TM (normal, retracted,

30 | www.PediatricSuperSite.com

PEDIATRIC ANNALS 39:1 | JANUARY 2010

3901Shaikh.indd 30

1/6/2010 3:06:19 PM

CM E

Figure 3. Acute otitis media. A. Bulging tympanic membrane. B. Bullous myringitis. C. Cobblestoning of the tympanic membrane.

with AOM.14 A Cochrane review of these studies found that although antimicrobials reduced the proportion of children experiencing ear pain at 2 to 7 days after diagnosis, the reduction was only modest (22% compared with 16%).14 However, in most of the studies included in this review, children with severe symptoms specically were excluded.15,16 Only a minority of children had bulging TMs. Because bulging of the TM a nding that is crucial for the diagnosis of AOM was not required, these trials may have permitted inclusion of children who did not actually have AOM but instead had OME in conjunction with an acute, unrelated, minor illness. Thus, it seems possible that children with severe AOM were systematically underrepresented in these placebo-controlled studies, resulting in an underestimation of differences in efcacy between placebo and antibiotics. A recently completed, large, placebo-controlled trial, which used stringent diagnostic criteria and a validated parent-reported symptom scale, may provide useful information to guide management of children with AOM. Some authors have recommended withholding antimicrobial treatment entirely in some or all cases of AOM unless symptoms persist or worsen. The evidence for this approach comes from three studies, all of which had important limitations. Two studies compared

immediate versus delayed antibiotic treatment for children with non-severe AOM.17,18 Parents of children in the watchful waiting or wait and see arm were instructed not to ll the antibiotic prescription unless symptoms failed to improve after 2 to 3 days of observation. In both studies, less than 50% of children had bulging TMs. In one, parents were not blinded to treatment allocation. Both studies had a disproportionately large number of children older than 2 years. Despite these limitations, all of which bias the results toward the null, both studies showed that antibiotics were more effective than watchful waiting. Children in the immediate antibiotics study arm appeared to improve 1 day earlier than children in the watchful waiting study arm. In the third study,19 in addition to the limitations mentioned, rather than using a symptom diary, as the rst two studies had done, parents were called by a research assistant 4 days after diagnosis to ascertain the presence or absence of otalgia and fever. Accordingly, changes in symptoms during the rst few days of therapy precisely when the largest differences are expected were not measured.13 It is therefore perhaps not surprising that little or no difference in symptoms was observed. In summary, although it may well be the case that children with non-severe AOM may be safely managed with a wait-and-

see approach, because of the limitations of the studies to date, further research is warranted before changes in routine practice can be recommended. SELECTING ANTIMICROBIAL THERAPY Choice of antimicrobial therapy is guided by knowledge of overall bacterial etiology, bacterial susceptibility, and expected spontaneous cure rates. Approximately 20%, 50%, and 90% of AOM episodes caused by S. pneumoniae, H. inuenzae, and M. catarrhalis, respectively, can be expected to resolve spontaneously.20 Amoxicillin, in higher doses (80 to 90 mg/kg/day in two divided doses), continues to be effective against susceptible, intermediately resistant, and some highly resistant strains of S pneumoniae.21 Its low cost, palatability, and side-effect prole make it an attractive choice for rst-line therapy for children with AOM. Oral cephalosporins and macrolides are generally less effective than high-dose amoxicillin, either because they are relatively ineffective against resistant strains of S. pneumoniae or because they do not provide reliable activity against betalactamase-positive H. inuenzae strains. These drugs may be appropriate for the penicillin-allergic patient but with close clinical follow-up. In children who are at high risk of treatment failure (eg, children who have

PEDIATRIC ANNALS 39:1 | JANUARY 2010

www.PediatricSuperSite.com | 31

3901Shaikh.indd 31

1/6/2010 3:06:21 PM

CM E
received treatment with a beta-lactam drug in the past month, or children with a history of recurrent AOM), treatment with amoxicillin/clavulanate potassium (90/6.4 mg/kg) should be considered. DURATION OF ANTIMICROBIAL THERAPY Thirteen studies have compared short (fewer than 7 days) versus long (at least 7 days) courses of antibiotics for AOM, of which only three blinded investigators and participants were included.15,22 In these three studies, children receiving a short-course of antibiotics had a higher likelihood of treatment failure, compared with children receiving longer course of antibiotics (odds ratio = 2.12; number needed to treat, 11).15 In addition to the limitations discussed with regard to the placebo-controlled studies, the studies were limited by the use of different denitions for treatment failure across studies. This makes it difcult to assess the risks and benets of short-course therapy. Further study is warranted in children to determine appropriate length of therapy for AOM. DIAGNOSTIC TYMPANOCENTESIS AND MYRINGOTOMY Diagnostic tympanocentesis and myringotomy, which involve puncturing or incising the TM, respectively, and aspirating middle ear uid to relieve pressure and permit the identication of infecting organisms, is indicated in children who do not respond to two courses of antibiotic therapy.23 Children with suppurative complications (mastoiditis, meningitis, labyrinthitis, and facial nerve paralysis) also benet from the reduction of middle ear pressure and precise ascertainment of the causative pathogen provided by tympanocentesis. USE OF ADJUVANT MEDICATIONS The use of antihistamines and/or decongestants does not appear justied in the treatment of AOM. Several placebo-controlled randomized trials and a meta-analysis failed to show any improvement in outcome associated with the use of these agents.24 Moreover, the use of decongestant and antihistamines is associated with signicant side effects, such as drowsiness, diarrhea, rash, dizziness, psychosis, and persistence of middle ear effusion.25 Two studies examined the use of analgesic otic drops in children with AOM.15,26-28 Children treated with analgesic drops were signicantly less likely
5. Chonmaitree T, Owen MJ, Patel JA, Hedgpeth D, Horlick D, Howie VM. Effect of viral respiratory tract infection on outcome of acute otitis media. J Pediatr. 1992;120(6):856-862. 6. Block SL, Hedrick J, Harrison CJ, et al. Community-wide vaccination with the heptavalent pneumococcal conjugate signicantly alters the microbiology of acute otitis media. Pediatr Infect Dis J. Sep 2004;23(9):829-833. 7. 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. 8. Pichichero ME, Casey JR, Hoberman A, Schwartz R. Pathogens causing recurrent and difcult-to-treat acute otitis media, 2003-2006. Clin Pediatr (Phila). 2008;47(9):901-906. 9. Shortridge VD, Flamm RK, Ramer N, Beyer J, Tanaka SK. Novel mechanism of macrolide resistance in Streptococcus pneumoniae. Diagn Microbiol Infect Dis. 1996;26(2):73-78. 10. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance--a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J. 1999;18(1):1-9. 11. 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. 12. Casselbrant ML, Mandel EM, Fall PA, et al. The heritability of otitis media: a twin and triplet study. JAMA. 1999;282(22):2125-2130. 13. Shaikh N, Hoberman A, Paradise JL, et al. Development and preliminary evaluation of a parent-reported outcome instrument for clinical trials in acute otitis media. Pediatr Infect Dis J. 2009;28(1):5-8. 14. Glasziou PP, Del Mar CB, Sanders SL, Hayem M. Antibiotics for acute otitis media in children. Cochrane Database Syst Rev. 2004(1): CD000219. 15. Shaikh N, Harvey K, Paradise JL, Hoberman A. The Cochrane Library and acute otitis media in children: an overview of reviews. Evidence-Based Child Health: A Cochrane Review Journal. 2009;4(2):390-399. 16. Wald ER. Acute otitis media: more trouble with the evidence. Pediatr Infect Dis J. Feb 2003;22(2):103-104. 17. 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. 18. 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. 19. Spiro DM, Tay KY, Arnold DH, Dziura JD, Baker MD, Shapiro ED. Wait-and-see pre-

Further study is warranted in children to determine appropriate length of therapy for AOM.
to report pain than children treated with placebo; the number needed to treat for a 50% reduction of pain was 5. However, the studies included only children older than 5 years. In addition, because of the small number of patients, condence intervals were wide. SUMMARY In an era of increased bacterial resistance, use of stringent criteria for distinguishing AOM from OME will result in more judicious use of antimicrobials. Amoxicillin (at higher dosages in young and also otherwise high-risk children) continues to be the standard regimen for treating AOM. REFERENCES
1. Teele DW, Klein JO, Rosner B. Epidemiology of otitis media during the rst seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis. 1989;160(1):83-94. 2. Paradise JL. Otitis media in infants and children. Pediatrics. 1980;65(5):917-943. 3. Paradise JL. Managing otitis media: a time for change. Pediatrics. 1995;96(4 Pt 1):712-715. 4. Bluestone CD. Pathogenesis of otitis media: role of eustachian tube. Pediatr Infect Dis J. 1996;15(4):281-291.

32 | www.PediatricSuperSite.com

PEDIATRIC ANNALS 39:1 | JANUARY 2010

3901Shaikh.indd 32

1/6/2010 3:06:25 PM

CM E
scription for the treatment of acute otitis media: a randomized controlled trial. JAMA. 2006;296(10):1235-1241. 20. Howie VM, Ploussard JH. Efcacy of xed 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. 21. Dagan R. The use of pharmacokinetic/pharmacodynamic principles to predict clinical outcome in paediatric acute otitis media. Int J Antimicrob Agents. 2007;30(Suppl 2):S127-130. 22. Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SE, et al. Short course antibiotics for acute otitis media. Cochrane Database Syst Rev. 2009:In press. 23. American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute otitis media. Pediatrics. 2004;113(5):1451-1465. 24. Coleman C, Moore M. Decongestants and antihistamines for acute otitis media in children. Cochrane Database Syst Rev. 2008(3): CD001727. 25. Chonmaitree T, Saeed K, Uchida T, et al. A randomized, placebo-controlled trial of the effect of antihistamine or corticosteroid treatment in acute otitis media. J Pediatr. 2003;143(3):377-385. 26. Bolt P, Barnett P, Babl FE, Sharwood LN. Topical lignocaine for pain relief in acute otitis media: results of a double-blind placebocontrolled randomised trial. Arch Dis Child. 2008;93(1):40-44. 27. Foxlee R, Johansson A, Wejfalk J, Dawkins J, Dooley L, Del Mar C. Topical analgesia for acute otitis media. Cochrane Database Syst Rev. 2006;3:CD005657. 28. Hoberman A, Paradise JL, Reynolds EA, Urkin J. Efcacy of Auralgan for treating ear pain in children with acute otitis media. Arch Pediatr Adolesc Med. 1997;151(7):675-678.

PEDIATRIC ANNALS 39:1 | JANUARY 2010

www.PediatricSuperSite.com | 33

3901Shaikh.indd 33

1/6/2010 3:06:25 PM

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.