Controversies in the Management of Otitis Media
Controversies in the Management of Otitis Media
Author: John G. O’Handley, MD, Program Director, Family Practice Residency, Mount Carmel Health System, Columbus, Ohio.
Peer Reviewers: Stanley C. Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford, Director, AIDS Community Research Consortium, and Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, Redwood City, CA; and Douglas R. Smucker, MD, MPH, Assistant Professor, Department of Family Medicine, University of Cincinnati, Ohio.
Editor’s Note—Otitis media is the most commonly diagnosed childhood bacterial illness and has increased from 9.91 million office visits in 1975 to an estimated 30 million office visits a year.1,2 Its incidence in all children may be as high as 93% and may be found in 5-10% of all well-baby visits.3,4 Polyethylene tube placement for otitis media with effusion is second only to circumcision as the most common surgical procedure performed in the United States.
Because otitis media is so common in our practices, it is possible that complacency can creep into our diagnosis and treatment of this condition. A certain amount of controversy exists regarding the treatment of patients with infection in the middle ear. Recently published reports exhibit substantial differences of opinion regarding the use of antibiotics in treating acute otitis media (AOM), otitis media with effusion (OME), and recurrent otitis media, as well as the optimum duration of treatment. This article reviews the epidemiology, etiology, clinical features, and differential diagnosis of otitis media, and focuses on the controversies surrounding the management of this extremely common disorder.
Epidemiology
Studies have shown that few children reach adolescence without at least one episode of AOM. A major study in Boston involving 2500 children found that 9% had at least one episode of AOM by age 3 months, 25% had at least one episode by age 6 months, 62% had at least one episode by 1 year of age, and 17% had recurrent AOM.4 By the age of 7, 93% had at least one episode of AOM and 75% had experienced recurrent infection.
Etiology
The primary reason for colonization of the middle ear with pathogenic bacteria is eustachian tube dysfunction. It occurs in infants and children mainly because of the abnormal tubal compliance, leading to collapse of the eustachian tube and delayed innervation of the tensor veli palatini muscle, which serves to open the tube. The three most common bacteria involved in AOM are Streptococcus pneumoniae, Hemophilus influenzae, and Moraxella catarrhalis. Anaerobic organisms, as well as viruses, can also contribute to the infection. Heikkinen and associates recently determined the prevalence of various respiratory viruses in the middle ear fluid of children (age 2 months to 7 years) with AOM.5 In 168 of 456 children, the etiology for their respiratory tract infection was viral. Respiratory syncitial virus was the most common virus found in middle ear fluid during AOM, followed by parainfluenza virus, influenza A or B virus, enteroviruses, and adenoviruses. The risk factors that lead to AOM are shown in Table 1.6 The factors that most increase the occurrence of AOM are child care outside the home and parental smoking.7
| Table 1. Risk Factors for Acute Otitis Media |
• Male gender |
| ____________________________________________________________________________ |
Clinical Features
Most commonly, a viral upper respiratory infection precedes AOM. Sudden development of ear pain and fever in one-third to one-half of patients can signal the onset of AOM. In infants, the symptoms can be less localized and can include irritability, vomiting, diarrhea, and fever.
Middle ear effusion (MEE) is the hallmark of otitis media. If MEE is associated with symptoms such as pain or fever, the condition is called acute otitis media (AOM). When MEE is asymptomatic, the condition is called otitis media with effusion (OME). Erythema of the tympanic membrane without associated MEE is myringitis or tympanitis.8
Examination of the tympanic membrane is best accomplished with pneumatic otoscopy to determine movement. A normal tympanic membrane is flaccid, and lack of motion when the ear is insufflated implies middle ear fluid. Tympanometry can also be used to assess MEE. Table 2 lists the signs and symptoms seen most commonly when there is inflammation and fluid in the middle ear.6
| Table 2. Common Signs and Symptoms of Inflammation and Fluid in the Middle Ear6 |
• Otalgia |
| _______________________________________________________________________ |
Differential Diagnosis
Although otalgia is the number one symptom of patients presenting with AOM, a substantial number of patients presenting with this symptom will have normal-appearing ear canals and tympanic membranes.9 When the ear appears normal, the physician must consider the possibility of referred pain to the ear.
The sensory innervation is supplied through a combination of cranial nerves five, seven, nine, 10 and the first-third cervical nerves. The convergence of these cranial and upper cervical somatic afferents into a common synaptic region can explain the occurrence of referred pain in the head and neck region. Common sources of referred otalgia include abscessed teeth, malocclusion, temporomandibular joint disorders, myofascial pain syndromes (especially in the masseter muscles), nasopharyngeal carcinoma, infections in the paranasal sinuses, pharynx and salivary glands, carotodynia, temporal arteritis, cervical arteritis, and neuralgias.10 The age of the patient can allow exclusion of many of the above possible causes.
Management
In most developed countries (except the Netherlands), the standard treatment for AOM is antibiotic therapy. However, in 1992, the U.S. Institute of Medicine warned of the growing threat posed by resistant bacteria, and, in 1996, the Centers for Disease Control in Atlanta convened the Drug-resistant Streptococcus Pneumoniae Therapeutic Working Group made up of pediatricians, family physicians, internists, and public health practitioners to determine how best to use antimicrobial resistance data to make informed decisions for treatment of AOM.11 Penicillin resistance has been found everywhere that surveillance data are available. The proportion of invasive disease caused by penicillin nonsusceptible S. pneumoniae (MIC ³ 0.1 mcg/mL) ranges from 8% to 34%, with the higher rates in children rather than adults, especially if the children are in day-care or have received antibiotic therapy within the preceding three months.12 Harrison and colleagues found the rate of ampicillin resistance of bacteria in effusions to be three times higher during recurrent AOM as compared to an initial untreated episode of AOM.13
S. pneumoniae is the pivotal organism around which the choice of a suitable antibiotic must be made. An estimated 40-50% of cases of AOM are caused by S. pneumoniae, whereas H. influenzae causes 20-30% and M. catarrhalis causes 10-15%.11 Even though approximately 35-90% of strains of the latter two organisms produce beta-lactamase, AOM caused by these pathogens is far more likely to resolve spontaneously. Cohen points out that most trials comparing two antibiotics fail to show any therapeutic difference even when in vitro activities are markedly different. He concludes that this is likely because most cases of AOM resolve spontaneously and because of the small number of patients in the cited studies.14
In a more recent study, Doern and associates reviewed 1047 respiratory tract isolates of S. pneumoniae from 27 U.S. medical centers and seven Canadian institutions collected between February and June of 1997.15 The mechanism of resistance to penicillin is the production of altered penicillin-binding proteins on the bacterial cell wall.16 This leads to resistance to other beta-lactams, including, in some cases, extended-spectrum, third-generation cephalosporins.17 Doern et al found a combined rate of intermediate plus resistant strains of S. pneumoniae between 24% and 67.8% for the centers that contributed at least 19 isolates. Individual rates of resistance to specific agents in the United States were: amoxicillin, 18.1%; cefaclor, 38.3%; cefuroxime, 19.5%; cefpodoxime, 18.6%; cefotaxime, 4%; macrolides, 13%; clindamycin, 3.5%; tetracycline, 10.2%; and trimethoprim/sulfamethoxazole (TMP-SX), 19.8%.15 It is assumed that in vitro resistance translates into clinical failure rates in treating otitis media, although there is some question of this. For pneumococcal pneumonia, the relationship between in vitro activity and clinical failure is not clear. In fact, a Spanish study found mortality rates to be no different between patients with pneumonia due to penicillin-susceptible vs. intermediate or highly resistant strains when high-dose penicillin was used.18 The use of amoxicillin in higher than the normal dose (40 mg/kg/d) for the treatment of otitis media has been advocated. Although the FDA has not approved amoxicillin at higher dosages, Dowell and colleagues advocate using amoxicillin at 80-90 mg/kg/d as first-line therapy for high-risk patients.11 Reasons for this recommendation are the long history of safety and efficacy of amoxicillin, the evidence of superior middle ear fluid concentrations (3-8 mcg/mL for at least three hours after the dose19), and the lack of any dose-related toxicity. High-risk patients would include those with recent antimicrobial exposure, age younger than 2 years, and day-care attendance. If the patient with AOM continues to have ear pain, fever, tympanic membrane redness, bulging, or otorrhea after three days of treatment with amoxicillin, it is considered a treatment failure. It is, therefore, important to instruct the family about these symptoms for follow-up and to instruct the family to call within 48 hours if the patient has not improved. Ideally, a tympanocentesis with a culture of middle ear fluid could identify the etiologic agent. In the absence of these data, a subsequent antimicrobial should be effective against beta-lactamase producing H. influenzae and M. catarrhalis and also should be effective against most drug-resistant S. pneumoniae. Agents that meet these criteria include amoxicillin-clavulamate in higher doses, cefuroxime, axetil, or IM ceftriaxone.6 S. pneumoniae resistance to TMP-SX and macrolides is more likely when patients have failed amoxicillin treatment, and, therefore, these agents are less likely to be effective in initial treatment failures.20
The only developed country that restricts the use of antibiotics for otitis media is the Netherlands, where the rate of resistance is one-third of that of other European nations.21
Two advocates for reconsidering the use of antimicrobials for all children with AOM are Jack Froom and Larry Culpepper, both family practitioners.21,22 They are vocal supporters of the Dutch treatment model and state that evidence is weak for the use of antibiotics based on seven randomized, blinded, placebo-controlled trials of AOM over the past 30 years. One study, a nine-country otitis media investigation involving 3660 children, showed that antimicrobials did not improve outcome at two months and there was no difference in rates of recovery for antimicrobial type or duration of administration.23 They do admit, however, that there is a definite short-term benefit for treatment of AOM with antimicrobials. They cite a study by Kaleida and Casselbrant, which showed an initial failure rate of 7.7% in the placebo group compared with only a 3.9% failure rate in the antibiotic-treated group.24 There was no significant difference between the groups in regard to effusion at six weeks (51.5% vs 45.9%) or in regard to recurrence (27.6% vs 27.9%). In children older than 2 years of age with severe AOM (pain or temperature higher than 39°C), the failure rate for placebo was 23.5% vs. 4.1% for the amoxicillin-treated group. Again, at six weeks, the differences between the two groups in regard to effusion and recurrence were not significantly different. Another article cited is by Burke and associates, which reports a failure rate of 14.7% at one week in the placebo group with AOM compared with a 1.7% failure rate in the antibiotic-treated group.25 Thereafter, there were no differences between the two groups for up to one year. Froom and Culpepper argue that these studies suggest that the short-term benefit is limited to less than 20% of children and no long-term benefits are reported.
Culpepper and Froom cite a meta analysis of 33 randomized trials.22 They found that antimicrobial treatment of AOM confers a short-term benefit in only one child out of seven. The study by Rosenfeld and colleagues shows that the spontaneous rate of complete resolution (exclusive of middle ear effusion) within 7-14 days after presentation was 81% in the groups without antibiotics or tympanocentesis and 94.7% when antibiotics were used.26 In addition, no significant differences were found among the various antibiotics including beta-lactamase-resistant antibiotics.
Froom and Culpepper acknowledge that the incidence of meningitis has dramatically decreased in the antimicrobial era. However, it is not clear if this decrease is due to antimicrobial treatment, changes in the natural history of AOM, changes in organism virulence, or increased host resistance.22 They cite a study from the Netherlands of 4860 consecutive patients not given antibiotics. Only one patient experienced mastoiditis and none developed meningitis.27 Although AOM and meningitis can occur together in a small group of children (2/1000), the routine use of oral antibiotics has not demonstrated more efficacy in preventing meningitis than selective use of antimicrobials, such as practiced in the Netherlands.
Even though these arguments appear cogent and the Dutch experience makes sense with lowered bacterial resistance to antimicrobials, there is still a definite short-term benefit to antibiotic use proven by the cited studies. Indeed, Paradise takes issue with Froom and Culpepper’s conclusions and states that they overlook or ignore key study results and limitations.28 Paradise systematically looks at the same studies, points out their flaws, and levels accusations of bias in selecting placebo groups and inadequate doses of amoxicillin in the studies. Paradise also criticizes Culpepper and Froom for dismissing failure rates between placebo-treated and antimicrobial-treated subjects of 23.5% vs. 4.1% and 14.4% vs. 1.8% as "minor."22 Paradise does not negate reasons for restricting antimicrobial use in the treatment of AOM but clearly states that lack of efficacy is a "nonfact" and should not be used to argue against antimicrobial use in AOM. The increasing resistance of S. pneumoniae to penicillin, the arguments of Froom and Culpepper, along with the Dutch experience, must make us pause and think before automatically prescribing an antimicrobial for AOM. Certainly, there are cases in which watchful waiting would be appropriate, especially when the symptoms of AOM are not severe, if the child is older than 2 years of age, if there has been no prior antimicrobial use, and if the child is not in a day-care setting. In those cases and where follow-up is certain, restricting the use of antimicrobials should be considered.
Duration of Therapy
The standard duration of antimicrobial therapy for AOM, until recently, has been 10 days. This length of time was extrapolated from the 10-day treatment for Group A beta-hemolytic streptococcal tonsillopharyngitis, which has been studied scientifically. But with AOM, as well as with the infected organs, the causative organisms are different and studies have not shown the necessity of 10 days of therapy. Carlin and associates studied 518 children 6 weeks to 12 years of age with AOM.29 They found that in the majority of children treated with antimicrobials, the middle ear became sterile 3-6 days after treatment initiation. They performed tympanocentesis at study entry, and if culture of ear fluid yielded a bacterial pathogen, repeated the procedure three and six days after treatment. They defined bacteriologic success as elimination of the bacteria from the middle ear after three days and clinical success as defined as absence of fever, otorrhea, and substantial irritability as reported by the parent. Two hundred ninety-three patients had pathogenic bacteria isolated from the middle ear fluid, and bacteriologic success occurred at 3-6 days in 253 patients (86%). The 40 failures occurred (with one exception) in children younger than 18 months of age. There were six beta-lactamase-producing pathogens among the bacteriologic failures, a rate similar to the bacteriologic successes. These findings are evidence that a shorter course of antimicrobial therapy can be effective in children older than 18 months.
In another study, Ingvarsson and Lundgren enrolled 297 children from age 6 months to 7 years treated for either five or 10 days with penicillin.30 Success rates were similar for both regimens—79% in the five-day group and 70% in the 10-day group. Relapses, otitis media with effusion, and percentage of failures were also similar.
Hendrickse and colleagues studied 113 children from age 1 month to 10 years.31 All patients except those with spontaneous discharge from the infected ear underwent tympanocentesis with bacterial sampling. They treated infected patients with cefaclor, 40 mg/kg/d, every 12 hours for either five or 10 days. Fifty-five percent of middle ear fluid grew S. pneumoniae or H. influenzae or both and 21% grew M. catarrhalis. Staphylococcus was seen in 31% of patients with spontaneously ruptured tympanic membranes. The failure rate in the five-day group was 10% (6 patients) and 6% (4 patients) in the 10-day group. These differences were not statistically significant. The failure rates among children with spontaneous perforation were significant (53% in the five-day group vs 8% in the 10-day group). Hendrickse et al concluded that a five-day course of antibiotics is sufficient for AOM except when there is spontaneous perforation of the tympanic membrane. Interestingly, they cultured 94 specimens of middle ear fluid for M. pneumoniae but this organism was not isolated from any patient.
Hoberman and associates assessed the efficacy of amoxicillin/clavulanate in treating AOM with five- and 10-day regimens.32 They studied 858 children ages 2 months to 12 years with one of three regimens: 1) amoxicillin/clavulanate at 40 mg/kg/d in three divided doses for 10 days; 2) amoxicillin/clavulanate at 45 mg/kg/d in two divided doses for 10 days; and 3) the same dose as no. 2 for five days. They found successful clinical responses in 71% of patients in the five-day bid group and in 86.5% of patients in the 10-day bid group. But the main differences were age related. Subjects younger than 2 years responded more favorably to the 10-day regimens as compared to subjects younger than 2 years who received five days of therapy (follow-up, 12-14 days). Hoberman et al concluded that the effect of age on favorable outcome is clearly disease-related rather than drug-related and recommend the 10-day course in any patient younger than 2 years of age.
A meta-analysis performed by Kozyrskyj and colleagues studied randomized, controlled trials from 1966 to 1997 that included subjects aged 4 weeks to 18 years with a clinical diagnosis of AOM, no treatment at the time of diagnosis, and randomization to less than seven days of antibiotic treatment vs. seven or more days of therapy.33 Fifteen oral beta-lactam antibiotic trials, four intramuscular ceftriaxone trials, and 11 oral azithromycin trials were evaluated. Kozyrskyj et al concluded that 44 children would need to be treated with the long course of therapy to prevent one treatment failure and that a five-day course of antibiotics is effective treatment for uncomplicated AOM in children. Kozyrskyj et al did not separate the children by age but did admit that "subgroup sample sizes were too small to provide a reliable estimate of the risk of treatment failure with a shortened course of antibiotics in children younger than 2 years or children with perforated eardrums."33
Paradise concludes that at any age, severity of the disease needs to be taken into account and states a five-day course of antibiotics can be indicated for children 6 years or older in the absence of complicating factors.34 Paradise is strongly against anything less than 10 days of treatment for children younger than 2 years of age. Between 2 and 6 years is a gray area. There is a fine line between undertreatment and overtreatment and many factors need to be taken into account when treating patients.
In summary, the evidence supports a five-day course of antibiotics for treatment of uncomplicated AOM in children older than 2 years of age. For patients with perforated tympanic membranes who have recurrent episodes of AOM, who are younger than 2 years old, or who have a delayed response to therapy, a 10-day course of antibiotics is indicated. Judgment and thorough clinical evaluation are necessary in every case.
Single-Dose Therapy
Studies that have looked at single-dose ceftriaxone at 50 mg/kg, intramuscularly for AOM compared to oral antibiotics have shown treatment outcomes that were not significantly different at one- and three-month follow-up.35-37 There has been some criticism of using such a broad-spectrum antibiotic against pathogens that are rather narrowly defined.38 Cost and pain at the injection site are other objections raised. Parents certainly prefer single-dose treatment for their children39 and compliance is assured. For a child who is not eating or who is vomiting, it is an attractive alternative to oral therapy. Single-dose therapy with Rocephin may also be used as a second-line treatment for AOM when clinical symptoms persist in the patient beyond three days.
Prophylaxis for Recurrent Otitis Media
Prophylactic treatment is another controversial subject. The accepted definition of recurrent otitis media is three episodes of AOM within a six-month period with complete resolution between episodes or four episodes within a year with resolution between episodes. The question arises whether prophylactic antibiotics for recurrent AOM are actually effective in preventing further disease. There is also concern about developing more resistant bacteria with this method. Numerous studies have evaluated the effectiveness of prophylactic treatment. Principi and associates compared the efficacy of daily single-dose amoxicillin, 20 mg/kg/d, to trimethoprim/sulfamethoxazole (TMP/SX), 12 mg/kg/d, and to placebo.40 Their single-blind, placebo-controlled, randomized study included 96 children ranging in age from 9 months to 5 years with three or more otoscopically and tympanometrically documented episodes of AOM in the preceding six months. Drugs were administered at bedtime for six months. A child was dropped from the study if he or she developed two episodes of AOM within a two-month period. Compliance was evaluated by checking the amount of medicine remaining in the bottle. In the amoxicillin group, nine of 33 children developed 11 episodes of AOM; in the TMP/SX group, nine of 33 experienced nine episodes of AOM; and in the placebo group, 19 of the 30 children developed 25 episodes of AOM. The differences were statistically significant. Children attending day-care had significantly better outcomes than children not attending. Principi et al recommend administration of prophylactic antibiotics to otitis-prone children, especially if they are younger than 2 years of age and attend a day-care center. The small number of patients in this study weakens the recommendations that Principi et al propose. One must use caution with TMP/SX because of the side effects of rash, urticaria, Stevens-Johnson syndrome, hepatic necrosis, generalized vasculitis, aplastic anemia, nephrosis, and hemolytic anemia in G6 PD-deficient patients. Since the 53rd edition of the Physicians Desk Reference (1999) specifically states the drug "is not indicated for prophylactic or prolonged administration in otitis media at any age," one runs a substantial risk if side effects occur.41 Sulfisoxazole (Gantrisin) does not have the same warning and has been used effectively for prophylaxis in penicillin-allergic patients.42
The results of a recent double-blind, randomized study countered the previous study supporting prophylaxis. Roark and Berman studied 194 children age 3 months to 6 years who had three episodes of AOM in the previous six months.43 Subjects received either: 1) placebo twice daily; 2) amoxicillin once daily plus placebo once daily; or 3) amoxicillin twice daily. The dose for amoxicillin was 20 mg/kg/d. Roark and Berman confirmed the diagnosis of AOM by pneumatic otoscopy and tympanometry when possible. They examined asymptomatic subjects monthly, but if symptoms of AOM developed, they were seen within 48 hours. Subjects were dropped from the study if two new episodes of AOM developed. They found that the proportion of otitis-free subjects did not differ significantly between the three groups. When Roark and Berman compared the results by season (winter, October to March and nonwinter, April to September) they also found no significant difference. The incidence densities of AOM among children younger than 1 year was actually higher in the treated group compared to the placebo group. The patients were not selected by attendance at day-care but the possibility of prophylaxis with antibiotics increasing the nasopharyngeal colonization of resistant organisms and the rate of new episodes is a consideration. Compliance is another issue that arises in prophylaxis because parents are expected to administer medication for extended periods. Roark and Berman urge caution with prophylaxis but do not rule it out entirely. They state that it should be individualized in light of emerging resistant bacteria.
Williams and colleagues also studied the prophylaxis controversy.42 Their meta-analysis of 27 studies published between 1966 and 1993 attempted to determine the efficacy of antibiotics for prophylaxis of recurrent otitis media and the treatment of OME in children. Nine studies of antibiotic prophylaxis with 958 patients favored antibiotic treatment. Studies that used sulfisoxazole tended to have a better outcome than those using other medications, but the differences were not statistically significant. The evidence from this meta-analysis is insufficient to recommend a specific duration of prophylaxis; however, the data seemed to favor treatment for less than six months.
In summary, for children with three or more episodes of AOM in six months or four episodes in 12 months, the first choice of antibiotic for prophylaxis is amoxicillin at 20 mg/kg/d for 3-6 months. For those children sensitive to penicillin or who have had a breakthrough on amoxicillin, the drug of choice is sulfisoxazole (50 mg/kg/d) once a day.44 Follow-up should be every 4-8 weeks and complete blood counts should be obtained at those times for patients on a sulfa drug.44 The optimal duration of treatment is a matter of judgment but, between three and six months, is currently thought to be effective.45 Although prophylactic treatment with antibiotics for recurrent otitis media is effective, the magnitude of the effect is limited, requiring the treatment of nine children to show an improved outcome in one.42
Treatment of Otitis Media with Effusion (OME)
Otitis media with effusion (OME) is a condition characterized by persistent fluid in the middle ear but without pain, fever, or redness of the tympanic membrane. OME usually arises after AOM but can occur in the absence of AOM.46 The common cold is the most frequent origin of OME. Evidence suggests that OME improves spontaneously in 90% of cases within six months. Allergy, subtle immunologic deficiencies, and genetic factors all play a role in OME.
The controversies surrounding antimicrobial treatment of AOM and use of antimicrobials for prophylaxis are real but pale in comparison to the brouhaha surrounding the treatment of OME, formally called serous otitis media. An article in the New England Journal of Medicine by Mandel and associates initiated the dispute.47 Five-hundred eighteen infants and children with OME were treated for two weeks with amoxicillin or placebo. Mandel et al reported the rate of resolution of MEE to be twice as high in those treated with amoxicillin with or without decongestant antihistamine, as in patients who received placebo. However, 69.8% of the amoxicillin-treated subjects still had effusion. Mandel et al concluded that amoxicillin increases to some extent the likelihood of resolution.
One of the original investigators in the study, Erden Cantekin, PhD, disagreed with the results of the study but was not allowed to publish his opposing views in the New England Journal of Medicine. It was not until four years later that he was given a voice in the Journal of the American Medical Association.48 Basing his conclusions on the same study as Mandel and associates, he stated "amoxicillin with and without decongestant-antihistamine combination is not effective for the treatment of persistent asymptomatic MEE in infants and children."47 Cantekin’s bone of contention was that significant differences between the amoxicillin and placebo groups were only seen when otoscopy was used as the diagnostic measure. When tympanometry was used to assess clearance of middle ear fluid, the difference between treatment groups was not significant. In addition, 32.8% of children treated with placebo showed improvement in hearing from entry to the four-week visit, whereas 30.7% of children treated with amoxicillin had hearing improvement at four weeks. Cantekin also addressed the recurrence of effusion that was greater in the amoxicillin group than in the placebo group. A second phase of Mandel’s study involved the use of erythromycin/sulfisoxazole and cefaclor. This phase of the study showed no difference in placebo or antibiotic-treated patients but was never reported.
The controversy continued when Mandel et al responded to Cantekin’s article.49 They stated that Cantekin et al "committed a series of methodological improprieties, invoked fallacious concepts and invalid assumptions, and inadequately represented the findings of cited studies." Mandel et al stated that part of the problem is the interpretation of the tympanogram, which has 15 numbered types involving different interpretations rather than the two dichotomous categories referred to by Cantekin. The 15 tympanogram types must be interpreted according to probabilities. Mandel et al also take issue with the claim of increased recurrence rate in the amoxicillin-treated patients and showed that it was 53.9% rather than "two to six times larger in the antimicrobial-treated groups than in the placebo group," which was 52.4%. Cantekin et al excluded children who developed AOM and disregarded recurrences beyond eight weeks even though follow-up continued to 16 weeks, according to Mandel et al. Other accusations by Mandel et al included use of fallacious reasoning to infer observer bias and misrepresentation of treatment results in studies of AOM.
Williams et al performed a meta-analysis of 12 studies in an attempt to resolve the controversy.42 Williams et al assessed short-term effects on the patient, short-term effects on the ear, and intermediate and long-term effects. Ten of the studies favored short-term antibiotics with the patient as the outcome measure. The studies that had the ear as the outcome measure showed effects from short-term antibiotic treatment in seven of eight studies. When evaluating intermediate to long-term effects, Williams et al found little evidence of benefit from antibiotic treatment of OME.
Although Williams et al tried to clear the air with their meta-analysis, it was not completely successful.42 A panel of experts convened by the Agency for Health Care and Policy Research (AHCPR) recommended antibiotics or observation after six weeks of OME with hearing evaluation being optional. After three months of OME documented by pneumatic otostopy or tympanometry, the patient should be referred for a hearing evaluation. If there is a 20 decibel or worse loss bilaterally, the patient should be treated with either antibiotics or bilateral myringotomy with tube placement. If OME persists at 4-6 months with hearing loss, then treatment should include bilateral myringotomy with tube placement.50 Culpepper and Froom disagreed with this recommendation.51 They pointed out that the AHCPR panel stated there was no sound research to support or refute the theory that OME results in speech or language delays or deficits. Furthermore, there is limited scientific evidence on which to base clinical care of children with OME. The panel made recommendations based on expert opinion by a majority of the panel members instead of basing the recommendations on consensus reached through discussion. Culpepper and Froom believed there was a disagreement between an interventionist approach and a prudent approach that shuns interventions of unproved benefits. They conclude that quality of life issues, symptoms, and family preferences play an important role in treatment and that these factors were not taken into account by the AHCPR panel. The evidence required for rational care of children with OME is not yet available. Froom and Culpepper advocate a less aggressive approach than that advocated by the AHCPR. They state that for the asymptomatic child with OME, no treatment might be the most appropriate and reasonable decision.51
Conclusion
What is a practicing clinician to do in the face of conflicting evidence in the literature that does not reach consensus? Being aware of the differing opinions is certainly an important start in making clinical decisions, which can have lasting implications on patients. To do no harm is a tenet that no physician disputes. The controversies surrounding otitis media have been presented not to confuse the reader but to make him or her aware of the options available for treatment. Many variables enter into the equation of patient care and those that relate to ear disease have been presented here. Availing ourselves of the information necessary to make knowledgeable decisions is the most important skill we can acquire.
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