Otitis Media in Children: Antimicrobial Strategies for Overcoming Barriers to Clinical Cure
Author: Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine; Associate Clinical Professor, Oregon Health Sciences University, Portland, OR.
Peer Reviewers: Larry B. Mellick MD, MS, FAAP, FACEP, Chief of Service and Chairman, Director of Pediatric Emergency Medicine, Department of Emergency Medicine, Medical College of Georgia, Augusta, GA.
Steven G. Rothrock, MD, FACEP, Research Director, Department of Emergency Medicine, Orlando Regional Medical Center & Arnold Palmer’s Hospital for Women and Children, Orlando, FL; Clinical Assistant Professor, Division of Emergency Medicine, University of Florida College of Medicine, Gainesville, FL.
Acute otitis media in children: common, confusing, costly, and controversial. Otitis media is both the most common bacterial infection in childhood and the most commonly diagnosed bacterial illness in the pediatric age group. More than one-half of infants will have at least one episode of acute otitis media before their first birthday, and more than 80% will report this infection by their third birthday.1 Even more problematic from a clinical perspective is that otitis media tends to be a recurrent illness of childhood, with about 50% of infected children having three or more episodes in their first three years of life and 17% having three or more episodes within a six-month period.2
Furthermore, antibiotic prescribing for otitis media is almost always empiric and rarely benefits from microbiologic identification or susceptibility results. Some cases may not require antibiotic therapy, although distinguishing among patients who do and do not require antimicrobial intervention can be a formidable clinical challenge. Even if an antibiotic with an appropriate spectrum of coverage is identified, there is always the "give-and-take" issue associated with antibiotic administrationparents have to "give" the antibiotic, and in turn, children must be willing to "take" the drug. This give-and-take interaction is fundamental to maximizing cure rates in the real-world environment.
Making matters worse is the difficulty of identifying an appropriate, cost-effective antibiotic that is "smart" enough to provide coverage against the most likely offending organisms in a particular patient. For example, in children with otitis media, a so-called "high-performing" antibiotic must be "smart" enough to cover appropriate species of Streptococcus pneumoniae, H. influenzae, and M. catarrhalis. Because time-honored agents such as amoxicillin have demonstrated inconsistent in vitro activity against beta-lactamase-producing bacterial isolates as well as S. pneumoniae, many experts have recommended elevation of advanced macrolides and third-generation cephalosporins to a first-line status.3-7
Finally, the road from the prescription pad to clinical cure depends on many factors beyond spectrum of coverage, including prescription, parent, patient, and drug resistance (PPPD factors). The PPPD approach to antimicrobial selection in otitis media attempts to account for all the factorsand potential barriersthat go into the equation for clinical cure, such as cost of the medication, compliance profile, palatability issues, duration of therapy, gastrointestinal side-effect profile, convenience of dosing, spectrum of coverage, and day care administration concerns. Overcoming these barriers to clinical cure is essential for enhancing clinical outcomes and reducing the costs of therapy and complications of the disease.
With these issues in mind, this articlewhich presents a thorough discussion of the pathophysiology, complications, and bacteriology of otitis mediaprovides a clinical overview of otitis media in children and outlines a rational, systematic approach to antimicrobial selection in this patient population.
The Editor
Not surprisingly, the costs of evaluating and managing otitis media are staggering. For example, in 1990, more than $3 billion was spent on antibiotics and surgical therapy in order to service approximately 25 million visits for acute otitis media.8 Moreover, the number of annual visits and the fixed-dollar costs of treating otitis media have risen dramatically over the past two decades. The placement of tympanostomy tubes remains extremely common, surpassed only by circumcision in frequency of pediatric surgical procedures. Somewhat less obvious, but significant from the parental perspective, are the economic opportunity costs associated with lost work time required by working parents who must care for ill children with acute otitis media.
Otitis media is not a benign disease. Of greatest concern is the potential for persistent middle ear effusions to result in hearing loss, which may lead to delays in language development and behavioral problems.9 Other complications include: tympanic membrane perforation, acute mastoiditis, cholesteatoma, meningitis, epidural abscess, and venous sinus thrombosis.
Few illnesses have engendered as much debate in the pediatric literature as the appropriate therapy for otitis media. In many countries, observation without antibiotic therapy is the treatment of choice for most ear infections. This approach has been advocated in the United States, and the increasing prevalence of multiple-drug-resistant strains of common bacterial pathogens has been cited as the inevitable consequence of our eagerness to initiate antibiotic therapy for a disease that is frequently self-limited. Well-respected authorities have called for modifying our management of otitis media, and the Agency for Health Care Policy Research has recently published guidelines for therapy of otitis media with effusion.10,11
Otitis media refers to a spectrum of processes characterized by inflammation of the middle ear and encompasses a wide scope of diseases. A number of schemes are used to further classify otitis media according to presence and duration of symptoms, physical findings, and risk of complications. The simplest, most widely used, and most practical of these divides the syndromes into two categories: acute otitis media and otitis media with effusion.
Acute Otitis Media. Acute otitis media is characterized by inflammation of the middle ear and, generally speaking, presents with the rapid onset of symptoms and signs of ear pathology. Fever and ear pain are the most common manifestations of acute ear infection. Infants may demonstrate ear tugging, while older children may verbally localize pain to the ear; however, many children manifest acute otitis media with nonspecific symptoms, including irritability, anorexia, vomiting, or diarrhea.12 Clearly, such symptoms may be seen with a number of other infectious processes, most commonly viral upper-respiratory infections.
It has been argued that because the symptoms associated with acute otitis media are so nonspecific, the aforementioned definition of acute otitis media is arbitrary and should be extended to include any patient with characteristic findings on otoscopic examination, regardless of other signs or symptoms of acute illness. When acute otitis is defined in this manner, one-third of cases have no associated symptoms.9 The majority of authorities, however, consider the acute onset of symptoms to be necessary in order to make the diagnosis of acute otitis media.9,10
Age Factors. Acute otitis media is most common in children 6 months to 3 years of age; by age 3 the vast majority of children have had at least one episode of acute otitis.1 There is marked seasonal variation in the occurrence of acute otitis media, with a peak in disease activity during winter and early spring months. This variation coincides with, and may be related to, the rate of viral upper respiratory infections.13 Seasonal variability may not be significant in infants under 1 year of age.14
Risk Factors. Certain factors predispose to acute otitis media. (See Table 1.) Native Americans have the highest rate of otitis media, while black children have one-half to one-third the incidence of white children.15 Infants who were exclusively breast fed for the first four months of life have half the number of cases of otitis media compared to non-breast-fed infants and 40% that of infants who had breast feeding supplemented with other foods.16 Supine bottle feeding as well as the use of pacifiers past the age of 10 months also predispose to ear infections.17,18
Day Care. Children attending day care develop acute otitis media far more frequently than children cared for at home.19 This has important public health implications, since each year an increasing percentage of American children are cared for outside the home. In 1986, for example, approximately 2.6 million children were enrolled in licensed and regulated day care centers, and an additional 2.7 million participated in unregulated day care programs.20 Children of mothers who smoke appear to have a greater risk of developing otitis media, although there are conflicting data.21,22 Other risk factors for development of acute otitis media include male sex, family history of recurrent otitis media, and having siblings.1 Certain craniofacial abnormalities, such as cleft palate, are also associated with recurrent episodes of acute otitis media.
Pathophysiology. The pathophysiology of acute otitis media is controversial and probably multifactorial. The underlying predisposing factor appears to be eustachian tube dysfunction resulting from either obstruction by hyperplastic adenoidal tissue or from intrinsic dysfunction that impairs the normal drainage of fluid from the middle ear. Abnormalities implicated in the pathogenesis of otitis media include defective innervation of the tensor veli palatini, adenoidal hypertrophy, ciliary dysfunction, and secretory IgA deficiency resulting in bacterial colonization of the nasopharynx.
Viral infection or allergic responses may cause changes in the mucosa of the nasopharynx, eustachian tube, and middle ear that enhance bacterial adherence and predispose to bacterial infection.23 Whatever the etiology, impairment of eustachian tube function leads to accumulation of fluid in the middle ear. Bacteria from the nasopharynx can then ascend and proliferate behind the tympanic membrane, resulting in acute infection.13
Otitis Media with Effusion. The second broad category of middle-ear infection, otitis media with effusion, is commonly defined as a chronic bacterial infection persisting more than two weeks. The syndrome usually develops as a result of acute otitis media but may develop without an acute antecedent infection.24 Other terms used for otitis media with effusion include secretory otitis, serous otitis, and chronic purulent otitis media.
The clinical hallmark of otitis media with effusion is an asymptomatic middle-ear effusion.12 While an occasional patient will present with the complaint of diminished hearing or sensation of fullness in the ear, the diagnosis is more typically made during a well-child examination or during a follow-up examination after an episode of acute otitis media.
Bacterial Etiology and Drug Resistance Issues
The most commonly isolated bacterial pathogens in both acute and recurrent otitis media are Streptococcus pneumoniae, Haemophilus influenzae (nontypable), and Moraxella catarrhalis.25,26 (See Table 2.) Consequently, first-line agents should demonstrate adequate in vitro coverage against this spectrum of organisms. In children between 1 month and 10 years of age, S. pneumoniae and H. influenzae each account for about 40% of infections; M. catarrhalis accounts for about 20%.26 It should be stressed that neonates may also develop infections with gram-negative enteric bacilli and Staphylococcus aureus, together accounting for 15-20% of otitis media cases in this age group.24 Other pathogenic bacteria include Streptococcus pyogenes and anaerobic organisms.9 Children under 6 years of age with patent tympanostomy tubes and acute symptoms have pathogens similar to other children, while Pseudomonas aeruginosa and Staphylococcus aureus are occasionally isolated from older children with tubes.27
Drug Resistance. Drug resistance among bacteria involved in otitis media is rapidly emerging.3,26 In this regard, beta-lactamase production is common among isolates of H. influenzae and M. catarrhalis, rendering about 30-50% of H. influenzae and up to 80% of M. catarrhalis isolates resistant to ampicillin.28 Although variable from patient to patient and region to region, these emerging resistance patterns may explain the failure rates associated with such traditional therapeutic measures as amoxicillin.3,26 Accordingly, the evolution of antibiotic-resistant bacterial strains implicated in otitis media has fueled interest in alternatives to amoxicillin, which, primarily because of its cost, has been the traditional first-line agent for this infection, despite showing increasing resistance. This problem can be circumvented by adding a beta-lactamase inhibitor such as clavulanic acid to amoxicillin (i.e., amoxicillin/clavulanate) or by choosing alternative antibiotics, among them, azithromycin, loracarbef, and second-generation cephalosporins.
Without question, a far more disturbing trend is the emergence of penicillin-resistant S. pneumoniae. Although the incidence of resistant strains demonstrates regional variations, the continued prevalence of S. pneumoniae as the principal etiologic agent in otitis media has important therapeutic implications, especially in light of the trend toward emergence of penicillin- and cephalosporin-resistant strains of this organism. From a clinical perspective, it should be emphasized that the development of penicillin-resistant strains has been associated with increased resistance to other beta-lactam antibiotics, including amoxicillin, cefaclor, cefuroxime, and cefixime, as well as the non-beta-lactam antibiotics trimethoprim-sulfamethoxazole and erythromycin.29,30
Based on currently available studies, about 25% of S. pneumoniae isolates obtained by tympanocentesis from patients with otitis media in various regions of the United States demonstrated intermediate or complete resistance to penicillin. Currently, intermediate or complete resistance to the advanced macrolides, azithromycin and clarithromycin, has been identified in about 5% of S. pneumoniae isolates, as compared to 15-25% of isolates shown to be resistant to such antibiotics as penicillin, amoxicillin, cefixime, trimethoprim-sulfamethoxazole, and other cephalosporins.3,20,26 These findings suggest that in vitro resistance patterns to S. pneumoniae are one factor that should be considered in the selection process of an antibiotic for treatment of otitis media.31 The only antibiotic to which drug resistance has not been found is vancomycin.
There may be several causes of multiple drug resistance among S. pneumoniae strains. Certainly the most likely culprit is the frequent use, or perhaps overuse, of multiple antibiotics for treating run-of-the-mill pediatric infections, some of which may not be bacterial in etiology. The use of multiple partial courses of antibiotic therapy is a pattern perpetuated by poor medication compliance or drug discontinuation which, as a rule, is associated with poor toleration of the medication, prolonged duration of therapy, inconvenient administration requirements (daily dose frequency), and/or excessive reliance on day care centers to administer part of the therapeutic course.5,6,10,29,32-35 Resistant pneumococcal strains are more prevalent among children recently treated with beta-lactam antibiotics.36 Children in day care easily infect one another with these resistant strains.37 The growing popularity of prophylactic antibiotic therapy for recurrent infections may have selected resistant strains of organisms. Finally, the widespread use of antibiotics in agriculture may have further contributed to the emergence of drug resistance.
Sterile and Viral Effusions. Not all cases of acute otitis media yield bacterial pathogens when aspirates from the middle ear are cultured. The rate of such "sterile" cultures varies dramatically between studies because of differences in bacterial isolation techniques and differences in the definition of acute otitis media. In a recent study investigating only children with acute signs and symptoms of illness, pathogenic bacteria were isolated from all but 10% of patients.38 The majority of studies, however, report culture-negative rates of 20-50%, and the accepted rate of sterile cultures in the literature is about 30%.12,39
Viruses have been identified as the sole infective organisms in 6% of cases of acute otitis media.40 Viral pathogens include parainfluenza, influenza, adenovirus, enterovirus, rhinovirus, and respiratory syncytial virus.23,24 It is generally believed that viral infections of the middle ear, often associated with viral upper-respiratory illness, predispose to bacterial superinfection that develops into acute otitis media.9 However, viral infection per se is considered an uncommon cause of acute otitis media in children.
Clinical Assessment and Diagnostic Strategies
A variety of techniques are available for quantifying tympanic membrane mobility and hearing deficits, two important clinical clues suggesting the presence of acute otitis media. Despite the high specificity and sensitivity associated with these findings, the pediatrician, family practitioner, or emergency physician can almost always confirm the diagnosis of otitis media using a simple pneumatic otoscope. In fact, a recent expert panel report has affirmed the reliability of diagnosing otitis using this device alone.11 Insufflation of air into a pneumatic otoscope with a rubber bulb allows the examiner to assess the mobility of the tympanic membrane while directly visualizing the membrane and external canal. The normal tympanic membrane is concave, translucent, and easily mobile with air insufflation.24 A light reflex in the inferior-anterior aspect of the membrane and the outline of the malleus within the middle ear are visible in the normal ear.
Inadequate visualization of the tympanic membrane may lead to errors in the diagnosis of otitis media. Adequate removal of cerumen using an ear spoon, curette, or warm water irrigation is essential. It is important to recognize that an injected tympanic membrane with normal mobility does not establish a diagnosis of otitis, as this finding commonly results from viral upper respiratory infections, the child’s crying, or local irritation from efforts to remove cerumen. A false impression of diminished tympanic membrane mobility may result from an inadequate seal between the otoscope speculum and the ear canal.9
Adjuncts to the diagnosis of otitis media are available but are not readily accessible to all physicians and are rarely necessary to make an accurate diagnosis in the ED. Tympanometry quantifies tympanic membrane mobility. Acoustic reflexometry uses reflected sound waves to detect middle ear effusion. Audiometry measures conductive hearing loss. These tools may be valuable in directing long-term therapy and determining the need for surgical intervention.41
The Ear Examination. A careful examination of the ear may not be possible without proper positioning of the child, which can be quite difficult in young and uncomfortable pediatric patients. To overcome possible resistance, many examiners place infants and younger children supine on an examination table, with the child’s arms immobilized at the elbows over the head or at the sides by a parent or attendant. With the examiner holding the infant’s head to one side, the mobility of the infant’s head and torso is thus greatly restricted. Older, more cooperative children can be examined in a parent’s lap, facing the parent and held tightly against the parent’s chest with one arm while the other holds the child’s head to one side. Retracting the pinna superiorly and laterally, which straightens the external canal, is particularly helpful for examining the ears of younger children.
The most specific sign of acute otitis media is diminished or absent mobility of the tympanic membrane with air insufflation.24 In otitis media, the tympanic membrane often appears dull and bulges externally, losing its concave contour and light reflex. The membrane itself may be red or yellow, and the bony landmarks are often obscured. Occasionally, an air-fluid level or air bubbles may be visualized behind the tympanic membrane. If the membrane has perforated, a purulent exudate may be seen in the external canal. Bullous myringitis, which is associated with Mycoplasma and viral infections, presents with large, brown, hemorrhagic bullae on the tympanic membrane.
Associated Clinical Findings. As discussed earlier, most pediatric experts consider associated signs or symptoms of acute illness to be necessary for the diagnosis of acute otitis media. While fever and ear pain or tugging are common, 30% of children with acute otitis media are afebrile and 40% have no apparent ear pain.42 Other signs include irritability, anorexia, vomiting, and diarrhea. Because of the non-specific nature of the associated findings and the frequency of otitis media in children, this disease is probably overdiagnosed. Otitis media is a common cause of febrile illness in children; consequently, physicians may be inclined to make the diagnosis of an ear infection as the cause of the fever, despite other clinical findings suggesting another diagnosis. A thorough, comprehensive physical examination and history are the best safeguards against over- or underdiagnosis of this important condition.
Otitis Media with Effusion. In the absence of symptoms or other signs of acute illness, evidence of middle ear inflammation is indicative of otitis media with effusion (OME). Typical findings of OME are diminished tympanic membrane mobility and visualization of air-fluid levels. OME may present with evidence of negative pressure in the middle ear, which is suggested by a more horizontal orientation of the malleus and enhanced mobility of the tympanic membrane when negative pressure in the external canal is created by insufflation.9 Associated symptoms may include a sensation of fullness in the ear or obvious hearing loss.
Managing Otitis Media: The Cases For and Against Routine Antibiotic Therapy
Who should be treated? When are antibiotics indicated, and when is watchful waiting with close follow-up the most appropriate course? The majority of pediatricians, family practitioners, and emergency physiciansand, in fact, many parents of children with otitis mediaare aware that the necessity to routinely treat otitis media with antibiotics has been the subject of heated debate over the past decade.
In this regard, a number of factors are widely cited as evidence that current indications for antibiotic treatment should be re-evaluated. Combining four placebo-controlled trials examining the effect of withholding antibiotic therapy in acute otitis media, 76% of untreated children demonstrated "spontaneous cure" or demonstrated significant improvement without treatment.43 A recent meta-analysis of 30 studies evaluating 5400 cases of acute otitis media found an 81% rate of spontaneous symptom resolution and improvement in the appearance of the tympanic membrane.44 While some of these spontaneously resolving cases may represent patients with ear infections of viral etiology, the high percentage of recovery without treatment suggests that a significant percentage of bacterial infections will also clear without antibiotic therapy.
These data have led some practitioners to view acute otitis media as a self-limited disease that does not generally require medical (i.e., antimicrobial) intervention. In Europe, particularly in Scandinavia and the Netherlands, watchful waiting is an accepted standard of care for acute otitis media. Most physicians in these countries will initiate antibiotic therapy only when fever and symptoms persist more than 24-72 hours or when complications develop.44-46 By withholding antibiotics for the majority of patients, it has been argued, unnecessary antibiotic treatment with its attendant costs and side effects is minimized, and the rise of multidrug-resistant bacterial organisms may be curtailed.
These studies, however, should be interpreted with great caution, since the majority of the trials included in the meta-analysis did not follow children over the long term and, therefore, could not evaluate the risk of recurrent infections, hearing loss, development of OME, and other complications. Accordingly, most experts in the United States do not favor withholding antibiotic therapy in acute otitis media.
Moreover, European studies, it has been noted, do not have sufficient power to detect low complication rates and represent only children not prone to recurrent infections.43,47 It is argued that complications such as intratemporal or intracranial infections, which are now rare, occurred in up to 20% of patients with acute otitis media in the pre-antibiotic era.43 In particular, antimicrobial therapy was largely responsible for reducing the incidence of mastoiditis as a sequela of otitis media from 17% to less than 1%.48 Furthermore, a recent rise in the number of cases of acute mastoiditis in German infants and children has been attributed to inadequate or absent antibiotic treatment of acute otitis media.49
In addition to the limitations of the aforementioned studies, recent investigations and meta-analyses demonstrate antibiotic therapy to be significantly more effective than a strategy of watchful waiting.40,44 Despite the high spontaneous cure rate, treatment with antimicrobial agents improves the incidence of symptom resolution in acute otitis media by about 15% and reduces treatment failure eightfold compared to observation alone.44,50 In light of these studies and given the dramatic reduction in complications since the introduction of antibiotics, most pediatric and emergency medicine authorities in the United States recommend routine antibiotic treatment for acute otitis media.10
The Pediatric Antimicrobial Armamentarium: Making Therapeutic Choices
Although one of the principal concerns in choosing antibiotic therapy is clearly the drug’s in vitro efficacy against the most likely infective organisms, many studies have found a number of available antimicrobial agents to be equally effective in treating otitis media.51 It should be noted that a drug’s efficacy in a clinical trial setting and its therapeutic worthiness in the real-world environmentwhich is saddled with well-recognized impediments to clinical cure such as day care-mediated administration of the drug, palatability of the medication, cost considerations, and discontinuation due to side effectsoften diverge depending on the clinical environment and patient population. Development of agents permitting more convenient administration but that also maintain in vitro coverage against the appropriate bacterial species represents an attempt to mitigate these potential barriers. In addition to the older, so-called "standard antibiotics,"most notable among them, the penicillins such as amoxicillin and sulfa drugsthere are many newer oral agents, particularly cephalosporins and macrolides, that play an important role in treating bacterial infections commonly encountered in children.
Typically, antibiotics have been evaluated by comparing spectrum of activity, clinical efficacy, toxicity (adverse drug reactions and interactions), pharmacokinetics, convenience, compliance with dosing, and cost. When antibiotics are indicated, the choice is often more complicated than it may seem to be on the surface.
The newer antibiotic suspensions, although possessing variable increases in the spectrum of activity and convenience factors over older agents, have uniformly been shown in clinical trials to be equally, but rarely more, efficacious than standard therapy. It should be stressed, however, that within the context of clinical trials, patients are frequently counseled and followed with pill counts to ensure compliance with their regimens. As a result, outcomes in these studies may deviate from those seen in the "real world," where noncompliance with antibiotics is a major barrier impeding the pathway from the prescription pad to clinical cure.33,35,52,53 Consequently, it may be difficult to extrapolate from cure rates published in idealized clinical trials to observed results at the front lines of clinical practice. A more comprehensive, outcomes-oriented approach, discussed below, attempts to account for all potential barriers that may potentially obstruct the journey from the prescription pad to clinical cure.
The PPPD Approach to Selecting Antimicrobial Suspensions in Children4,32-35,52,54-64
PPPD Resistance Barriers for Oral Antibiotic Therapy. In the best and most cost-effective of all worlds, the antibiotic selection process for acute otitis media would be based on an outcome-oriented assessment of the total cost of cure for this common, and sometimes recurrent and distressing, infection in the pediatric age group. (See Table 3.) Close examination of Table 3 underscores the importance of identifying therapeutic agents that, because of favorable cost, compliance, and coverage features, are able to reduce barriers to clinical cure. Antimicrobial agents that satisfy these criteria will improve "first time around" cure rates and thereby reduce overall outcome costs.
Among the factors that would be included in such an outcome analysis (i.e., the total costs associated with diagnosis, management, and cure of otitis media) are the following: cost of the medication used for the initial course of therapy, cost of the initial physician visit, human resource time (telephone time, revisits, etc.) required to service queries regarding the drug and/or its side effects, the cost of practitioner re-evaluations for treatment failures, the cost of additional courses of therapy for therapeutic failures, the economic opportunity cost sustained by parents because of time lost from work to care for their child, the cost of medications or other devices (diapers, etc.) to service the gastrointestinal side effects (diarrhea) of the medication, and the short- and long-term sequelae of treatment failure or repeated episodes of infection (hearing loss, linguistic difficulties, typanostomy tubes, mastoiditis, otitis media with effusion, etc.).
Although comprehensive, outcome-directed studies addressing all of these variables for acute otitis media are not currently available, other outcome-sensitive drug therapy assessment tools can be pressed into service for the purpose of drug selection. In this regard, the prescription, parent, patient, and drug resistance (PPPD) approach to drug selection permits pediatricians, family practitioners, and pediatric emergency physicians to evaluate and compare the clinical success profiles (CSPs) of one antibiotic vs. another. (See Table 4.) These comparisons are based on a synthetic approach constructed according to established specifications and parameters such as price, daily dose frequency, duration of therapy, palatability, side-effect profile, and spectrum of coverage.33,35,55,56,61-64
From the perspective of overcoming barriers to clinical cure, in order for patients with otitis media to complete the journey from prescription pad to cure, several real-world resistance barriers must be negotiated. In other words, the patient will have to overcome PPPD barriers in order to achieve an optimal clinical outcome. Using this cost-effectiveness and real-world-oriented approach, some antibiotics will fare well, whereas others will encounter more formidable resistance barriers on the road to clinical cure.
From the perspective of prescribing antibiotics in the outpatient setting, it must be emphasized that each of these four resistance barriers is important, and that if one or more of these barriers (cost, side-effect profile, lack of convenience, inadequate coverage) is of sufficient magnitude, it may influence the overall real-world cure rate.34,35,56,63 These barriers are discussed in the following sections.
Finally, it should be stressed that ensuring medication compliance in a young child requires collaboration between parent and child. This is called the "give and take" of antibiotic compliance in the pediatric age groupparents have to want to "give" the drug, and the child has to want to "take" it. If the parent, guardian, or caregiver encounters sufficient impediments to drug administration, or if the patient encounters palatability or side effect problems that compromise ingestion, compliance with drug regimen may be compromised.
Prescription Resistance. Prescription resistance refers to the likelihood that the parent will actually fill the prescription for their child. In general, the greater the acquisition cost for a course of therapy, the less likely they are to fill their prescription.57-59 Studies show that up to 25% of patients given a prescription for an antibiotic never even fill the prescription, and the risk of non-filling increases with the cost of the medication.62 Accordingly, the primary determinant of prescription resistance is the cost of the medication.
In this regard, the issue of cost has become especially important in the age of managed care and increased emphasis on outcome-effectiveness. For the purposes of generating the PPPD profiles for oral suspensions, the author has chosen $40 per course of therapy as a cutoff mark for prescription resistance. Although generic preparations of amoxicillin, for example, are available for as little $6-9 per course of therapy, other non-generic preparations in the cephalosporin class routinely fall in the $45-65 price range.
Cost differences of this magnitude usually are perceived as significant, from an institutional, physician, and patient perspective. Accordingly, in an attempt to highlight the substantial differences in antibiotic acquisition cost, antibiotics have been grouped into broad categories costing less than $40 and those costing more than $40, in order to indicate the relative degree of prescription resistance.
In addition to the cost of the antibiotic, other factors that also may affect the parent or guardian’s propensity for filling the prescription include: 1)The clinical provider’s persuasiveness in convincing the parent that the child needs the antibiotic as part of their therapeutic program;63 2) the word of mouth about the drug (i.e., is it perceived by the community as a tolerable or poorly tolerated medication); 3) previous experiences with the medication; and 4) the parent’s perception of the seriousness of their child’s condition.29,32,55,58,59,62
Parent Resistance. Because children do not self-administer medications, compliance in the pediatric age group depends, to a great extent, upon the parent’s willingness and motivation to give the antibiotic. In this regard, at least one study has shown that poor medication compliance is the most common cause of antibiotic treatment failures.65 Drugs that require too many doses, too many days, and produce too many side effects can deter parents from administering a full course of therapy.29,32,34,35,52
Similarly, medications that require refrigeration, must be administered by day care or school personnel, or require special timing requirements with respect to food intake, increase parent resistance and, therefore, may compromise proper, timely administration.32,34,52,65 In particular, drugs with gastrointestinal side effectsespecially diarrheacreate a "clean-up" factor that may discourage parents from completing the entire course of therapy as prescribed.
The potential problems associated with day care-mediated (i.e., child care settings) administration of oral suspensions should be mentioned. Clearly, transportation of the medication to and from a child care facility, refrigeration requirements, dosing schedule, and administration by day-care employees can affect clinical outcome.32-34 Consequently, the only so-called "day care-proof" antibiotic is the one whose dosing schedule permits the entire course of the medication to be administered by parents outside the day care environment. Generally speaking, once-daily medications (cefpodoxime, azithromycin, etc.) are optimal in this regard, whereas medications dosed on a TID basis (amoxicillin, erythromycin-sulfisoxazole) may be associated with suboptimal administration and, therefore, inconsistent compliance patterns.33,34
Although once-daily medications are associated with the best compliance profiles, antibiotics dosed on a twice-daily basis are also acceptable in most circumstances and introduce minimal, but statistically significant, changes in medication intake. One landmark study evaluating compliance alterations in short-term antibiotic regimens demonstrated that the proportion of non-compliers increased from about 2% to 25% when the daily dose frequency increased from once to twice daily.32 However, significant alterations in compliance patterns that are clinically important usually are more likely to occur when daily dose frequency increases from a BID to TID pattern.32-34
Patient Resistance. Patient resistance refers to the likelihood that the child will actually want to take the medication. The principal factors determining patient resistance in the pediatric patient are palatability (taste and consistency of the suspension) and gastrointestinal side effects (nausea, abdominal cramping, diarrhea, etc.). Or, as one experienced clinician has put it, it’s a matter of "palatability and poopability, of taste and waste." As might be expected, in the pediatric patient, poor palatability can adversely affect patient compliance.33,34,52,55 For example, parents who perceive that their child "dislikes" the medication may have trepidations about "forcing" the drug upon them. Alternatively, infants who find oral suspensions to be distasteful may spit up portions of the dose, a response that can produce suboptimal drug intake, unless expelled doses are vigorously replenished by the parent. Examples of medications that have been associated with poor palatability, bitter taste, a high incidence of GI side effects, or less-than-optimal consistency (granular taste, bitterness, etc.) include clarithromycin, cefpodoxime, erythromycin, amoxicillin-clavulanate, and cefprozil.35,52,55
The effect of the patient resistance (i.e., compliance profile) barrier on clinical outcomes in outpatient infections should never be underestimated. Even when the cost of the medication is sufficiently low to encourage prescription fulfillment, if patient resistance factors are sufficiently imposing, clinical cure rates may be compromised.
Drug Resistance. Drug resistance refers to the spectrum of coverage (i.e., in vitro antimicrobial activity) provided by the antibiotic against the most likely bacterial pathogens encountered in a specific infection. Although in vitro sensitivity to pathogens does not necessarily correlate with clinical cure rates, susceptibility results should be considered when making an antibiotic selection. For example, organisms targeted for empiric therapy in otitis media in children older than 6 months include S. pneumoniae, H. influenzae (including beta-lactamase producing species), and M. catarrhalis.3,26,29,30 Generally speaking, an antibiotic with proven activity against all three organisms would provide optimal coverage and, therefore, would be associated with a low drug resistance barrier. On the other hand, an antibiotic with activity against only two of these organisms might produce therapeutic failures in a significant percentage of cases.
Naturally, drug resistance must always be considered when selecting an antibiotic. Even when the medication is inexpensive and well-toleratedi.e., prescription, parent, and patient resistance barriers are lowif the drug fails to provide optimal activity at the business end (i.e., it has poor spectrum of coverage against anticipated organisms at the site of infection), cure rates will be less than optimal.
Optimal PPPD Profiles.54 Optimal PPPD profiles are characterized by antibiotics with low prescription, parent, patient, and drug resistance barriers. In this regard, the most desirable agentin other words, the antibiotic producing the greatest likelihood of clinical success in the real-world patient encounterwill satisfy the following criteria: 1) It will be priced attractively enough to encourage prescription filling and/or its cost is sufficiently competitive to ensure formulary acceptance at cost-sensitive, managed care health plans and HMOs; 2) it is easy enough to store, prepare, and give to encourage parental administration; 3) it is sufficiently well-tolerated by the patient to promote ingestion of the drug without undue patient resistance; and 4) the agent demonstrates in vitro activity against all the anticipated bacterial pathogens in acute otitis mediaS. pneumoniae, H. influenzae (including beta-lactamase producing species), and M. catarrhalisso that its empiric use will provide appropriate coverage with initial therapy, thereby reducing the necessity for pharmacologic reservicing due to treatment failures.
PPPD Profiles of Antibiotic Suspensions Used To Treat Otitis Media
Based on the parameters outlined above, it is possible to categorize and compare antibiotic suspensions according to whether and how consistently they satisfy specific PPPD criteria. (See Table 5.) Brief PPPD summaries, in alphabetical order, of currently available antibiotics analyzed according to these criteria are presented below.
Amoxicillin. Still considered by some authorities to be the initial drug of choice for acute otitis media,51 the increasing in vitro resistance to this and other beta-lactam antibiotics among H. influenzae and M. catarrhalis species, and, more recently, S. pneumoniae, should be noted. In addition, alternative drugsespecially the newer macrolides azithromycin and clarithromycin, which demonstrate in vitro efficacy against many beta-lactamase-producing organismsshould be considered in communities with a high prevalence of resistant organisms. The PPPD profile reflects the fact that amoxicillin is price attractive from a prescription resistance standpoint and that it has excellent palatability. But it also reflects the possible compliance-compromising effects of TID dosing and the problematic in vitro resistance patterns to commonly implicated bacterial pathogens.3,5,6,26,66,68
With respect to bacterial resistance, it should be stressed that although in vitro susceptibility patterns with amoxicillin point to possible windows of bacterial vulnerability in terms of coverage, in vitro results are not always predictive of clinical cure rates. In this regard, amoxicillin has been widely used with a high degree of clinical success as an initial agent to treat acute otitis media.
Amoxicillin-Clavulanate. The cost of amoxicillin-clavulanate recently has been lowered. A typical course of therapy for most children is less than $40, which is reflected in the prescription resistance barrier. Although palatability of the drug is quite acceptable, the incidence of diarrhea is reported in large studies to be about 16%.5 Recent approval for BID administration of this antibiotic should be noted, although this agent does not share the full compliance-promoting benefits of once-daily administration seen with other agents. Appropriate in vitro coverage of most bacterial offenders causing acute otitis media is reflected in the favorable rating in the drug resistance category.
Amoxicillin-clavulanate is now made in a 200 mg/5 mL and 400 mg/5 mL suspension. This new suspension has a lower concentration of clavulanate and thus has fewer GI side effects (especially diarrhea). Furthermore, dosing differs for these two new suspensions. Otitis media should be treated with 45 mg/kg BID, a more convenient dosing pattern than the previous TID recommendations, if these suspensions are used. Finally, the new suspensions contain aspartame and should not be used by phenylketonurics.
Azithromycin. Approved in suspension form for the treatment of acute otitis media in children, the advanced macrolide (azalide) azithromycin has a highly favorable PPPD profile among antibiotic suspensions indicated for the treatment of this infection. The cost for a course of therapy is less than $40, and the once-daily, five-day course introduces compliance-enhancing features that, to a great degree, permit parental, day care, and grade school drug administration problems to be circumvented.6,69 A well-accepted palatability profile, combined with an overall discontinuation rate of about 0.9%, justify a favorable rating in the patient resistance category.3,20,26 From the perspective of drug resistance, this agent is characterized by excellent in vitro coverage of beta-lactamase-producing H. influenzae and M. catarrhalis, as well as in vitro coverage of S. pneumoniae, for which the overall resistance rate is estimated to be about 5%.3,20,26,66,67
Although this second-generation macrolide has been used widely in the adult population, azithromycin oral suspension for children only recently has become available for use in the United States by pediatric practitioners. The advantageous PPPD profile for this new macrolide is supported by rigorous clinical studies that have been published comparing the safety and efficacy of azithromycin to amoxicillin-clavulanate for the treatment of acute otitis media in children.3,5,68 In these large trials, clinical cure rates of up to 87.5% are reported, and azithromycin was as effective as, but better tolerated than, amoxicillin-clavulanate for the treatment of acute otitis media in the pediatric age group.4-6,68 Azithromycin does not affect a single IV dose of theophylline. However, caution is advised against the use of the two drugs if multiple doses of theophylline are used.
Cefaclor. Because cefaclor is now available in a generic preparation, its cost profile has become more favorable (i.e., it generally costs less than $40 for a course of therapy). The 10-day BID or TID dosing schedule is not optimal from a compliance profile standpoint, although palatability of the drug is good. With respect to drug resistance, there has been emergence of resistance to some S. pneumoniae species and to selected beta-lactamase-positive producing strains of H. influenzae and M. catarrhalis.3,6,26
Cefixime. The cost of a 10-day course of therapy may be associated with significant prescription resistance in price-sensitive populations and institutions. Its once-daily dosing schedule and good taste are advantages, but emerging resistance to S. pneumoniae should be considered a possible cause for treatment failures.3,6,26,70,71 In light of its inconsistent in vitro activity against S. pneumoniae, some experts do not recommend this antibiotic as first-line therapy for otitis media.70,72
Cefpodoxime. An appropriate spectrum of in vitro coverage and once-daily dosing schedule are reflected in the excellent parent- and drug-resistance categories. The taste of this suspension has been reported to be less than desirable in some studies,26,52,55 and the cost for a course of therapy is significantly greater than for such agents as amoxicillin, azithromycin, and trimethoprim-sulfa.
Cefprozil. Cost may be a barrier to some patients and cost-sensitive institutions. Spectrum of in vitro coverage is advantageous. However, the BID dosing schedule is not as parent-friendly as that offered by once-daily preparations, and a less-than-optimal palatability profile for cefprozil has been reported in some studies.26,52,55,73
Ceftriaxone. Ceftriaxone is not available as a suspension, but it has been employed for management of acute otitis media. A single IM dose of ceftriaxone appears to effective against acute otitis media and may be an appropriate choice for therapy when there is a high risk of medication noncompliance.74
Cefuroxime. The spectrum of in vitro coverage against organisms implicated in acute otitis media in children is good, and palatability is acceptable. Cefuroxime requires BID dosing and is more costly than a number of available agents.
Clarithromycin. Although regional variations may exist, in vitro susceptibility testing suggests that more strains of S. pneumoniae are susceptible to the macrolides clarithromycin and azithromycin than to such other agents as penicillin, cefixime, and cefaclor.6 Moreover, in vitro activity of clarithromycin against M. catarrhalis is excellent. And while in vitro activity of this macrolide against H. influenzae is sufficient, more than one in vitro assessment study suggests azithromycin is more active against H. influenzae than clarithromycin, which may have important therapeutic implications.3,6,69 Nevertheless, like azithromycin, clarithromycin also has been shown to produce comparable cure rates to amoxicillin-clavulanate.7 Finally, the potential for drug-drug interactions between clarithromycin and theophylline, terfenadine, or astemizole requires caution.
From a prescription resistance perspective, the cost for a course of therapy for clarithromycin is significantly more than it is for amoxicillin, trimethoprim-sulfamethoxazole, or azithromycin. Finally, with respect to medication compliance, BID dosing is less desirable than once-daily administration,64 and unpleasant taste and palatability problems have been described for clarithromycin.52,55,73
Erythromycin-Sulfisoxazole. Although reasonably priced at less than $40, this combination antibiotic requires a TID or QID dosing schedule, and gastrointestinal side effects associated with the erythromycin component may affect patient compliance.13,14,46 The PPPD profile reflects these clinical resistance barriers, as well as the inconsistent in vitro coverage of beta-lactamase-producing H. influenzae and S. pneumoniae isolates found in otitis media. Ventricular arrhythmias may be seen with the macrolides clarithromycin or erythromycin in combination with over-the-counter anticholinergics or antihistamines such as terfenadine.7
Loracarbef. The principal barrier to initial use of loracarbef is its cost. The BID dosing schedule can be problematic in some cases. The favorable taste of the medication and its consistent in vitro activity against common middle ear pathogens are reflected in favorable designations in the patient and disease resistance categories.
Trimethoprim-sulfamethoxazole (TMP/SMX). Widely used for the treatment of acute otitis media, TMP/SMX is a fixed combination of trimethoprim and sulfamethoxazole in a ratio of 1:5. This antibiotic blocks sequential steps in folic acid synthesis. Oral TMP/SMX may rarely cause nausea and vomiting, and may produce depression of all bone marrow cell lines and hemolytic anemia, especially in patients with G-6-PD deficiency. Patients with HIV have a higher rate of skin rash, fever, leukopenia, and elevated serum tansaminase levels than non-HIV-infected patients. TMP/SMX may increase phenytoin levels and the dosage should be altered for patients with renal dysfunction. The highly attractive pricing profile (< $10 in most cases) and fairly consistent in vitro activity against expected organisms are reflected in the PPPD profile. As discussed, BID dosing is not optimal, and the risk of allergic reactions, although rare, should be considered.
Antibiotics of Choice. The outcome-sensitive, cost-effective oriented criteria considered in the PPPD system can be used to guide initial selection of antibiotics for otitis media. (See Table 6.) Because price is an important issue, especially in managed care environments, Table 6 presents therapeutic recommendations that have been broken down according to price categories (i.e., suspensions costing < $40 for an entire course vs those costing > $40).
Until recently, many authorities considered amoxicillin to be the drug of first choice for acute otitis media because of its efficacy, low cost, and tolerability.51 A more critical look at changing clinical patterns and the introduction of new antimicrobial options has forced a re-evaluation of this agent’s time-honored position among many pediatric and infectious disease experts.64,71 Nevertheless, because amoxicillin has been an institution in the therapeutic arsenal for otitis media, it probably justifies inclusion among first-line options costing less than $40 per course of therapy, but with some reservations.
In particular, the trend toward increasing in vitro resistance to amoxicillin among S. pneumoniae and beta-lactamase producing H. influenzae isolates found in the middle ear, combined with the introduction of advanced-generation macrolides, justifies a prudent reconsideration of amoxicillin’s role as the initial drug of choice for this condition. In this regard, amoxicillin may be a less-than-optimal initial agent in patient subgroups at higher risk for treatment failure due to poor medication compliance and in communities where a high percentage of penicillin-resistant S. pneumoniae isolates have been documented.30,34,52,64
Primarily because of cost and tolerance, many experts and institutions still position amoxicillin as their initial agent. But because of the aforementioned concerns, it is appropriate to designate an additional antibiotic suspension as a first-line drug in the less-than-$40 category. Based on its PPPD profile, which reflects a reasonable acquisition cost ($28.40 per course of therapy), its once-daily, five-day therapeutic course, low discontinuation rate (< 1% due to side effects3,4,26), efficacy studies confirming cure rates comparable to amoxicillin-clavulanate, and consistent in vitro activity against implicated bacterial species, azithromycin justifiably can be positioned as a first-line agent for acute otitis media in children.5,68,69 Antibiotics such as TMP-SMX can be very useful when cost issues predominate in drug selection and in patients with penicillin allergies.9
Among medications usually costing in excess of $40 for a course of therapy, first-line agents would include loracarbef and cefuroxime. These agents are well-tolerated and demonstrate excellent cure rates. Second-line agents in this category include clarithromycin and cefpodoxime, both of which may pose palatability problems. Cefpodoxime has the advantage of once-daily dosing.
Complications and Other Clinical Interventions
Refractory Acute Otitis Media. As a rule, antibiotic therapy should result in resolution of fever, symptoms, and signs of tympanic membrane inflammation within two days. Refractory acute otitis media is defined as persistent signs or symptoms of otitis after 48 hours of antibiotic therapy. Treatment failure is seen in about 10% of cases and is more likely when a viral organism or both viral and bacterial organisms have been isolated from the middle-ear aspirate.9 Confirmation of refractory acute otitis media indicates the need to change antibiotics. One option is to use an alternative first-line antibiotic, switching, for example, from amoxicillin to azithromycin or TMP-SMX, or to use one of the first-line antibiotics, such as loracarbef or amoxicillin-clavulanate, which are associated with greater cost. It should be stressed that none of the currently available oral suspensions is uniformly effective against highly resistant strains of S. pneumoniae.
Patients whose symptoms continue following completion of a second antibiotic and who have evidence of persistent otitis media on examination are candidates for tympanocentesis.9 This procedure permits isolation of the bacterial pathogen and determination of antibiotic sensitivity. Tympanocentesis is also indicated in the initial evaluation of a neonate with acute otitis media, as well as older infants and children who appear septic, display signs of suppurative complications, or are immunocompromised.75 Occasionally, this procedure may be useful for decompressing an extremely painful middle-ear effusion.
Recurrent Acute Otitis Media. A new episode of acute otitis media is one that begins at least 21 days following the diagnosis of the previous episode.1 Recurrent acute otitis media is defined as the development of at least three episodes of the illness within a six-month period.9 It is logical to treat a recurrent infection with a different antibiotic regimen than that used for the previous episode, employing either a different first-line antibiotic or a second-line agent as outlined for the treatment of acute otitis media refractory to therapy.
Acute Otitis Media in Children with Tympanostomy Tubes. Children under 6 years of age with acute symptoms and functioning tympanostomy tubes may be successfully treated with one of the systemic antibiotic regimens described above, although some physicians will add or substitute a topical agent. Older children, in whom Pseudomonas and S. aureus infections are not uncommon, are usually prescribed topical antibiotics with or without a systemic agent.27 A number of caveats regarding topical therapy for otitis media are discussed below.
Prophylactic Therapy. Patients with recurrent infections may be candidates for prophylactic antibiotic therapy, in which low doses of antimicrobials are administered for 3-6 months to prevent further episodes of acute otitis media. Several studies and a recent meta-analysis have concluded that antibiotic prophylaxis is effective in reducing both recurrent acute illness and the development of otitis media with effusion.76 Prophylaxis may be initiated in susceptible children at the onset of upper respiratory infection symptoms or administered continuously throughout the winter months.77,78
Otitis Media with Effusion. Otitis media with effusion does not cause immediate morbidity and does not warrant urgent antibiotic therapy. However, the risk of long-term complications has made this disease the subject of intense discussion in the pediatric and otolaryngologic literature for the past few years.9,10
Middle ear effusions are associated with significant hearing loss, ranging from 25 to 35 dB. Fortunately, the deficit is usually temporary and does not produce serious consequences. Persistent effusions, however, may result in delay of speech or language development.9,10 Episodes of otitis media with effusion early in life are associated, albeit weakly, with both abnormal speech and language development in younger children (< 4 years of age) and with behavioral problems in older children (> 4 years ).11 An expert panel reviewing treatment options for otitis media with effusion in young children concluded that combination antibiotic and steroid therapy is more effective than treatment with either placebo or antibiotic alone.79,80 The panel suggests considering antibiotic or combination antibiotic and steroid therapy in children with middle-ear effusions lasting at least three months when associated with bilateral hearing loss of ³ 20 dB.
Myringotomy and tube placement is another option for young children with otitis media with effusion and should be considered when bilateral effusions last at least four months and are associated with significant hearing loss (³ 20 dB). Adenoidectomy may be recommended for children at least 4 years of age and is as effective alone as when combined with tonsillectomy.11 Other experts suggest that surgical therapy should be considered only when a trial of antibiotic therapy has been unsuccessful.10
Analgesia. Analgesia is often necessary for children with acute otitis media, especially during the first 24 hours after initiation of antibiotic therapy.9 Acetaminophen or ibuprofen suspensions are often effective. A topical analgesic-anesthetic combination such as antipyrene and benzocaine solution (Auralgan) may be helpful but should be avoided if a perforated tympanic membrane is detected or believed to be likely.
Topical Antibiotics. Topical antibiotics are often employed to supplement oral therapy when the tympanic membrane is perforated or tympanostomy tubes are in place, and occasionally when otorrhea is noted.81 It should be stressed that topical therapy does not add significant antimicrobial activity to systemic antibiotic treatment for acute otitis media when the tympanic membrane is intact.43 The most commonly used topical antibiotic, neomycin-polymixin B-hydrocortisone (Cortisporin), contains propylene glycol, which has been shown to be toxic to the cochlea in experimental models and may actually cause middle ear inflammation and cholesteomas.82,83 While findings have not been seen in humans, they suggest that topical antibiotics should be used with caution.9,27 Topical therapy may be useful in treating chronic otorrhea, which should suggest Pseudomonas or S. aureus infection, which is etiologically distinct from acute otitis media.
Antihistamines and Decongestants. Antihistamines and decongestants have not been found in controlled studies to be useful in acute otitis media. Furthermore, a recent expert panel report recommends that such agents not be used for children with otitis media with effusion.11
Corticosteroids. Corticosteroids given systemically are effective for otitis media with effusion when used in conjunction with antibiotics. Given the absence of demonstrated efficacy and the risk of immunocompromise during an acute bacterial illness, their use is not recommended in acute otitis media.
The most common complications of otitis media are hearing loss and perforation of the tympanic membrane, which usually heals spontaneously. The most common infectious complication of acute otitis media is mastoiditis, which is suggested by tenderness over the mastoid process and by clouding of the mastoid air cells on plain radiographs or CT.24 Acute mastoiditis generally requires inpatient therapy with intravenous antibiotics; surgical intervention may be required. Cholesteatoma, a middle-ear mass composed of desquamating epithelium or keratin, is another complication of recurrent acute otitis media and may require surgical therapy.
Other complications of otitis media have become relatively uncommon since the widespread routine use of antibiotics. Meningitis may result from direct or hematogenous spread of bacterial pathogens from the middle ear. Contiguous spread of organisms may also cause brain abscess, subdural empyema, lateral venous sinus thrombosis, or facial nerve injury.24,81
It should be noted that the presence of otitis media does not necessarily rule out a coexisting serious bacterial infection. Importantly, up to one in five children with meningitis also have physical exam evidence of otitis media. In fact, the coexistence of these disorders may lead to an increased misdiagnosis rate for bacterial meningitis.
The majority of children with acute otitis media can be treated successfully as outpatients. Indications for hospitalization include toxic appearance, refractory vomiting, severe volume depletion, and intracranial or intratemporal extension, including acute mastoiditis and meningitis.
Febrile neonates in the first month of life with otitis media should be managed as inpatients because of their relatively immunocompromised state and because of the risk of sepsis from gram-negative organisms and S. aureus. Afebrile neonates under 1 month of age with otitis can be treated as outpatients if they are well-appearing and have close follow-up.13 Selected febrile infants between 4 and 12 weeks of age can be treated for acute otitis media as outpatients, provided they are non-toxic in appearance, have a white blood cell count of less than 15,000 cells/mm3, and have been carefully evaluated to exclude other sources of infection (including examination of cerebrospinal fluid, if indicated).84 It is imperative that discharged neonates have a reliable caretaker with a telephone and that prompt follow-up is assured.
Older infants and children with acute otitis media who are well-appearing, have no underlying disease, and an otherwise normal examination do not require further laboratory evaluation in the ED. Well-appearing febrile children with otitis media have the same rate of occult bacteremia as well-appearing febrile children with no obvious source for their infection. Complete blood counts, which generally show a mild leukocytosis, and blood cultures are not routinely indicated, and results do not correlate with severity of illness or risk of complications.
Follow-Up. Upon discharge, parents and caretakers of children treated for acute otitis media should receive careful discharge instructions highlighting potential problems related to treatment failure. In order to identify patients with infections refractory to initial antibiotic therapy, parents should be instructed to return for re-evaluation if fever, ear pain, or other signs and symptoms of acute infection are persisting 48 hours after initiation of antibiotic therapy. Parents should also be instructed to return for re-evaluation immediately if the child exhibits evidence of worsening illness, including rising temperature, increasing irritability, anorexia, vomiting, or the development of lethargy.
Signs and symptoms of infection will resolve within two days in most children treated for acute otitis media. Assuming that the child recovers as expected, a follow-up examination in 2-3 weeks is generally recommended. The purpose of the re-evaluation is to document resolution of infection and to detect chronic effusion or other sequelae of acute otitis media.
The necessity for routine follow-up in all cases of acute otitis media has recently been questioned. In healthy children over 15 months of age, parental impression of infection resolution and absence of symptoms appear to be accurate predictors of otitis resolution. Therefore, routine follow-up visits at 2-3 weeks may only be required of children 15 months of age or younger, those who have persistent symptoms of otitis media, or whose parents believe that the infection has not resolved.85 Children not meeting these high-risk criteria would still require follow-up at a later date to assess for persistent effusion, but this visit can be delayed for up to three months.
References
1. 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;160:83-94.
2. Alho OP, Koivu M, Sorri M. What is an "otitis-prone" child? Int J Pediatr Otorhinolaryngol 1991;21:201-209.
3. Neu HC. Otitis media: Antibiotic resistance of causative pathogens and treatment alternatives. Pediatr Infect Dis J 1995;14:S51-56.
4. Mclinn S. Double blind and open label studies of azithromycin in the management of acute otitis media in children: A clinical review. Pediatr Infect Dis J 1995;14:S62-66.
5. Hopkins SJ, Williams D. Clinical tolerability and safety of azithromycin in children Pediatr Infect Dis J 1995;14:S87-91.
6. Khurana CM. Issues concerning antibiotic use in child care settings. Pediatr Infect Dis J 1995;14:S34-38.
7. Aspin MM, Hoberman A, McCarty J, et al. Comparative study of the safety and efficacy of clarithromycin and amoxicillin-clavulanate in the treatment of acute otitis media in children. J Pediatr 1994;125:136-141.
8. National Center for Health Statistics. Office Visits for Otitis Media: United States, 1975-90. Advance Data from Vital and Health Statistic. No. 214. Hyattsville, MD: Public Health Service; 1992. (DHHS pub. no. 92-1250.)
9. Berman S. Otitis media in children. N Engl J Med 1995;332:1560-1565.
10. Paradise JL. Managing otitis media: A time for change. Pediatrics 1995;96:712-715.
11. The Otitis Media Guideline Panel. Clinical Practice Guideline, Otitis Media with Effusion in Young Children. Rockville, MD: Agency for Health Care Policy and Research; 1994. (AHCPR pub. no. 94-0622.)
12. Bluestone CD, Klein JO. Otitis Media in Infants and Children. 2nd ed. Philadelphia: WB Saunders; 1995.
13. Fleisher GR. Infectious disease emergencies. In: Fleisher GR, Ludwig S, eds. Textbook of Pediatric Emergency Medicine. 3rd ed. Baltimore: Williams & Wilkins; 1993.
14. Williamson HA, DePra J, Sulzberger LA. Lack of seasonal variability for recurrent otitis media in very young children. J Fam Pract 1991;33:489-493.
15. Bluestone CD, Klein JO. Otitis media, atelectasis and eustachian tube dysfunction. In: Bluestone CD, Stool SE, Scheetz MD, eds. Pediatric Otolaryngology. 2nd ed. Philadelphia: WB Saunders; 1990:320-486.
16. Duncan B, Eu J, Holberg CJ, et al. Exclusive breast-feeding for at least 4 months protects against otitis media. Pediatrics 1993;91:867-872.
17. Niemela M, Uhari M, Mottonen M. A pacifier increases the risk of recurrent acute otitis media in children in day care centers. Pediatrics 1995;96:884-888.
18. Tully SB, Bar-Haim Y, Bradley RL. Abnormal tympanography after supine bottle feeding. J Pediatr 1995;126 (Suppl.):105-111.
19. Stahlberg MR, Ruuskanen O, Virolainen E. Risk factors for recurrent otitis media. Pediatr Inf Dis 1986;5:30-32.
20. Data on file. New York. Pfizer, Inc.
21. Ey JL, Holberg CJ, Aldous MB, et al. Passive smoke exposure and otitis media in the first year of life. Pediatrics 1995;95:670-677.
22. EPA Report. Respiratory health effects of passive smoking. Passive Smoking and Acute and Chronic Middle-Ear Disease. Washington, DC: US EPA; 1992:7.4.
23. Swanson JA, Hoecker JL. Otitis media in young children. Mayo Clin Proc 1996;71:179-183.
24. Stair TO. Otolaryngologic disorders. In: Rosen P, Barkin RM, eds. Emer gency Medicine. 3rd ed. St. Louis: Mosby-Year Book; 1992:2460-2466.
25. Bluestone, et al. Ten-year review of otitis media pathogens. Pediatr Infect Dis J 1992;11:S7-11.
26. Barry AL, et al. In vitro activity of 12 orally administered antibiotics against four species of respiratory pathogens from US medical centers in 1992 and 1993. Antimicrob Agents Chemother 1994;38:2419-2425.
27. Mandel EM, Casselbrant ML, Kurs-Lasky M. Acute otorrhea: Bacteriology of a common complication of tympanostomy tubes. Ann Otol Rhinol Laryngol 1994;103:713-718.
28. Jacoby GA. Prevalence and resistance mechanisms of common bacterial respiratory pathogens. Clin Infect Dis 1994;18:951-957.
29. Caputo GM, Singer M, White S, et al. Infections due to antibiotic-resistant gram-positive cocci. J Gen Intern Med 1993;8:626-634s.
30. Friedland IR, McCracken GH. Management of infections caused by antibiotic-resistant Streptococcus pneumoniae. N Engl J Med 1994;331:377-382.
31. Nelson CT, Mason EO, Kaplan SL. Activity of oral antibiotics in middle ear and sinus infections caused by penicillin-resistant Streptococcus pneumoniae: Implications for treatment. Pediatr Infect Dis 1994;13:585-589.
32. Cockburn J, Gibberd RW, Reid AL, et al. Determinants of non-compliance with short-term antibiotic regimens. BMJ Clin Res 1987;295:814-818.
33. Chater RW. Dosing tips for tots. Am Pharm 1993;NS33:55-56.
34. Greenbery RN. Overview of patient compliance with medication dosing: A literature review. Clin Ther 1984;6:592-599.
35. Finney JW, Friman PC, Rapoff MA, et al. Improving compliance with antibiotic regimens for otitis media: Randomized clinical trial in a pediatric clinic. Am J Dis Child 1985;139: 89-95.
36. Breiman RF, Butler JC, Tenover FC, et al. Emergence of drug-resistant pneumococcal infections in the United States. JAMA 1994;271:1831-1835.
37. Reichler MR, Allphin AA, Breiman RF, et al. The spread of multiply resistant S. pneumoniae at a day care center in Ohio. J Infect Dis 1992;166:1346-1353.
38. DelBeccaro MA, Mendelman PM, Inglis AF, et al. Bacteriology of acute otitis media: A new perspective. J Pediatr 1992;120:81-84.
39. Schwartz R, Stool S, Rodrigues W, et al. Acute otitis media: Toward a more precise definition. Clin Pediatr 1981;20:549-554.
40. Ruuskanen O, Arola M, Heikkinen T, et al. Viruses in acute otitis media: Increasing evidence for clinical significance. Pediatr Infect Dis J 1991;10:427.
41. Shapiro AM, Bluestone CD. Otitis media reassessed. Postgrad Med 1995;97:73-82.
42. Heikkinen T, Ruuskanen O. Signs and symptoms predicting acute otitis media. Arch Pediatr Adolesc Med 1995;149:26-29.
43. Giebink GS, Canafax DM, Kempthorne J. Antimicrobial treatment of acute otitis media. J Pediatr 1991;119:495-500.
44. Rosenfeld RM, Vertrees JE, Carr J, et al. Clinical efficacy of antimicrobial drugs for acute otitis media: Meta-analysis of 5400 children from 33 randomized trials. J Pediatr 1994;154:355-367.
45. Van Buchem FL, Dunk JHM, Van’t Hof MA. Therapy of acute otitis media: Myringotomy, antibiotics, or neither. Lancet 1981;ii:883-887.
46. Van Buchem FL, Peters MF, Van’t Hof MA. Acute otitis media: A new treatment strategy. BMJ 1981;290:1033-1037.
47. Giebink GS, Le CT. Risk of mastoiditis in typical otitis media not managed by antibiotics. Lancet 1982;i:111.
48. Rudberg RD. Acute otitis media: Comparative therapeutic results of sulfonamide and penicillin administered in various forms. Acta Otolaryngol 1954;113(Suppl):9-79.
49. Hoppe JE, Köster S, Bootz F, et al. Acute mastoiditisRelevant once again. Infection 1994;22:178-182.
50. Burke P, Bain J, Robinson D, et al. Acute red ear in children: Controlled trial of non-antibiotic treatment in general practice. BMJ 1991;303:558-562.
51. Anonymous. Drugs for treatment of acute otitis media in children. Med Lett Drugs Ther 1994;36:19-21.
52. Nelson, JD. Clinical importance of compliance and patient intolerance. Infect Dis Clin Pract 1994;3:158-160.
53. Osterholm MT, Reves RR, Murph JR, et al. Infectious diseases and child care. Pediatr Infect Dis J 1992;11:S31-41.
54. Bosker G. Pharmatecture: Minimizing Medications to Maximize Results. St. Louis: Facts and Comparisons; 1996.
55. Demers DM, Scotik Chan D, Bass JW. Antimicrobial drug suspensions: a blinded comparison of taste of twelve pediatric drugs including cefixime, cefpodoxime, cefprozil, and loracarbef. Pediatr Infect Dis J 1994:13:87-89.
56. Chinburapa V, Larson LN. The importance of side effects and outcomes in differentiating between prescription drug products. J Clin Pharm Ther 1992;17:333-342.
57. Beardon PH, McGilchrist MM, McKendrick AD, et al. Primary noncompliance with prescribed medications in primary care. BMJ 1993;307:846-848.
58. Berg JS, Dischler J, Wagner DJ, et al. Medication compliance: A healthcare problem. Ann Pharmacother 1993;27:S1-24.
59. Litchman HM. Medication noncompliance: A significant problem and possible strategies. R I Med 1993;76:608-610.
60. McNally DL, Wertheimer D. Strategies to reduce the high cost of patient noncompliance. Md Med J 1992;41:223-225.
61. Anonymous. Writing prescription instructions. Can Med Assoc J 1991;44:647-648.
62. Coleman TJ. Non-redemption of prescriptions. BMJ 1994;308:135.
63. Roth HP, Caron HS. Accuracy of doctor’s estimates and patients’ statements on adherence to a drug regimen. Clin Pharm Ther 1978;23:361-370.
64. Eisen SA, Miller DK, Woodward RS, et al. The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med 1990;150:1881-1884.
65. Bluestone CD, Klein JO. Management. In: Otitis Media in Infants and Children. Philadelphia: WB Saunders; 1988:121-201.
66. Anonymous. Drugs for treatment of acute otitis media in children. Med Lett Drug Ther 1994;36:19-21.
67. Physicians’ Desk Reference. 50th ed. Oradell, NJ: Medical Economics Co; 1996.
68. Khurana C, McLinn S, Block S, ET AL. Trial of Azithromycin (AZ) vs Augmentin (AUG) for treatment of acute otitis media (AOM) [Abstract M61-64] Presented at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, FL, October 4-7, 1994.
69. Brown SD, Burton P, Rich T, et al. Susceptibility surveillance of US respiratory pathogen isolates to newer macrolide and azalide antibiotics. Presented at the 94th General Meeting of The American Society for Microbiology, Las Vegas, NV, May 23-27, 1994.
70. Khurana CM. Issues concerning antibiotic use in child care settings. Pediatr Infect Dis J 1995;14:S34-38.
71. McCarty JM. Bacterial susceptibility and tympanocentesis in acute otitis media. Pediatr Infect Dis J 1995;14:S45-50.
72. Talan D. The Manual of Emergency Medicine Therapeutics. St. Louis: Mosby; 1995:411.
73. Schentag JJ. Antibiotic treatment of acute otitis media in children: Dosing consideration. Pediatr Infect Dis J 1995;14:S30-33.
74. Green SM, Rothrock SG. Single-dose intramuscular ceftriaxone for acute otitis media in children. Pediatrics 1993;91:23-30.
75. Quayle KS, Fuchs S, Jaffe DM. Otitis and pharyngitis in children. In: Tintinalli JE, ed. Emergency Medicine. 4th ed. New York: McGraw Hill; 1996:604-611.
76. Williams RL, Chalmers TC, Stange KC, et al. Use of antibiotics in preventing recurrent acute otitis media and treating otitis media with effusion: A meta-analytic attempt to resolve the brouhaha. JAMA 1993;2700:1344-1351.
77. Biedel CW. Modification of recurrent otitis media by short-term sulfonamide therapy. Am J Dis Child 1978;132:681-683.
78. Berman S, Nuss R, Roark R, et al. Effectiveness of continuous vs. intermittent amoxicillin to prevent episodes of otitis media. Pediatr Inf Dis 1992;11:63-67.
79. Berman S, Grose K, Nuss R, et al. Management of chronic middle ear effusion with prednisone combined with trimethoprim-sulfamethoxazole. Pediatr Infect Dis J 1990;9:533-538.
80. Lambert PR. Oral steroid therapy for chronic middle ear effusion: A double-blind cross-over study. Otolaryngol Head Neck Surg 1986;95:193-199.
81. Kligman EW. Treatment of otitis media. Am Fam Physician 1992;45:242-250.
82. Masaki M, Wright CG, Lee DH, et al. Effects of otic drops on chinchilla tympanic membrane. Arch Otolaryngol Head Neck Surg 1988;8:1-5.
83. Wrights CG, Halama AR, Meyerhoff WL. Ototoxicity of an ototopical preparation in a primate. Am J Otolaryngol 1987;8:56-60.
84. Baker MD, Bell LM, Avner JR. Outpatient management without anti biotics of fever in selected infants. N Engl J Med 1993;329;1437-1441.
85. Hathaway TJ, Katz HP, Dershewitz RA, et al. Acute otitis media: Who needs post-treatment follow-up? Pediatrics 1994;94:143-147.
Physician CME Questions
7. Otitis media with effusion is characterized by:
A. fever.
B. ear pain or tugging.
C. non-specific signs and symptoms of infection.
D. a middle ear effusion without symptoms.
8. Which of the following is one of the most common complications of otitis media?
A. Perforation of the tympanic membrane
B. Brain abscess
C. Cholesteatoma
D. Meningitis
9. Examination of the ear in children with acute otitis media commonly reveals each of the following except:
A. a bulging tympanic membrane.
B. an absent light reflex.
C. clear bony landmarks.
D. an air-fluid level behind the tympanic membrane.
E. a hyperemic tympanic membrane.
10. Regarding the microbiology of acute otitis media:
A. bacterial beta-lactamase production is uncommon.
B. S. aureus infection is common in older children.
C. M. catarrhalis is a common pathogen.
D. viral organisms are the sole cause of most infections.
E. penicillin-resistant S. pneumoniae is rare.
11. Acute otitis media that does not respond to initial antibiotic therapy:
A. is an indication for corticosteroid therapy.
B. is an indication for myringotomy with tube placement.
C. renders other first-line antibiotics inappropriate.
D. is seen in at about 10% of cases.
E. frequently results in permanent hearing loss.
12. Indications for patient reevaluation after 48 hours of antibiotic therapy for otitis media include:
A. rising temperature.
B. increasing irritability.
C. development of lethargy.
D. development of anorexia and vomiting.
E. all of the above.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content