This report was reviewed for medical and scientific accuracy by Amisha Malhotra, MD, Associate Professor of Pediatrics, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Expert Commentary

George H. McCracken, Jr., MD, Professor of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas

The American Academy of Pediatrics/American Academy of Family Physicians will soon issue new guidelines for the treatment of acute otitis media in children. These new guidelines will lend more support for observation (withholding of antibiotics) in the case of the child (≥2 years of age) with certain diagnosis who is not seriously ill, or the child (non-severe) with an uncertain diagnosis (≥6 months of age).¹ For children in whom a course of antimicrobial therapy is deemed clinically appropriate, the guidelines will recommend high-dose amoxicillin (Amoxil®) (90 mg/kg/day in two divided doses for 5 to 10 days) as the first-line treatment option for acute otitis media.² For those patients with uncertain or history of non-type 1 penicillin allergy, first-line treatment options include cefdinir (Omnicef®), cefuroxime axetil (Ceftin®) or cefpodoxime (Vantin®). For those patients with severe allergy or history of anaphylaxis to penicillin, alternative treatment options include macrolide- or sulfonamide-based therapy. For treatment failures, recommended treatment options include high-dose amoxicillin/clavulanate (Augmentin ES®) (90 mg/kg/day in two divided doses), cefdinir, cefuroxime axetil, cefpodoxime, or ceftriaxone (50 mg/kg intramuscularly daily for 1 to 3 days).

Among the revisions in the new guidelines is the inclusion of specific oral cephalosporins as alternative initial therapy and upon failure of initial therapy for acute otitis media. Among the cephalosporins, all of the recommended agents offer comparable efficacy. Therefore, any differentiation between the agents will most likely center on other factors. For example, the palatability of an antibiotic, mostly determined by taste, is an important factor to consider because it enhances adherence to the prescribed regimen and therefore treatment outcome.

During the American Academy of Pediatrics 2003 National Conference and Exhibition, an interactive symposium using an Audience Response System (ARS) was conducted with several recognized authorities on otitis media to discuss the new recommendations and what they will mean to the practicing clinician. Altogether, the intent of the new guidelines is to give clinicians guidance in diagnosis and treatment of pain (ie, pain management) along with more flexibility in treating acute otitis media, to provide support for observation when appropriate, and to guide the selection of the most effective antibiotic therapy. This Pediatric Press Newsletter shares their insights.

Treatment versus Observation

"In the new treatment guidelines for acute otitis media, observation without antibacterial treatment in a child with uncomplicated acute otitis media will be an option for selected children, based on diagnostic certainty, age, severity of illness and assurance of follow-up," stated S. Michael Marcy, MD, Clinical Professor of Pediatrics, University of Southern California School of Medicine, Los Angeles, California.¹

In considering acute otitis media, the new guidelines will recommend antibacterial treatment for all infants less than 6 months of age. This includes children for whom the diagnosis of acute otitis media is established (full or bulging ear drum with reduced mobility, which is red or accompanied by pain that is adequate to interfere with sleep or day-to-day activities) or whose diagnosis is uncertain. Antibacterial therapy will also be recommended for children 6 months to 2 years with established diagnosis of acute otitis media, and for those with an uncertain diagnosis but present with severe illness. For children aged 2 years and older, when the diagnosis is certain, antibacterial treatment is recommended for severe illness only; observation should suffice for non-severe illness. Older children with an uncertain diagnosis should be observed only, Dr. Marcy explained.

"Observation is only appropriate, of course, for patients who you know and for whom you have assurance of follow-up," added Dr. Marcy.

Dr. Marcy noted that clinical trials have failed to demonstrate outcomes with antibiotic therapy that are substantially better than observation alone (placebo treatment). The most significant study, a 1991 trial by Kaleida et al³ involving nearly 540 patients aged 7 months to 12 years showed clinical resolution of acute otitis media (symptom relief) in 96% of children treated with amoxicillin at 2 to 3 days, versus 92% receiving placebo (patients younger than 2 years did not receive placebo). This amounts to a 4% advantage for treatment over observation in the first several days; the combined results from studies examining the differences at 4 to 7 days also show little or no advantage to antibiotics, Dr. Marcy advised.

Clinical differences emerge, however, when children less than 2 years of age are studied, especially those with severe illness. The new guidelines, therefore, will still recommend antibacterial treatment in that population. "This is potentially a high-risk group, an unknown entity, and we don't want to risk it," Dr. Marcy commented, noting that the main reason you treat infants is to prevent complications and speed the resolution of pain and symptoms.

Program co-chair Jerome O. Klein, Professor of Pediatrics, Boston University School of Medicine, Boston, Massachusetts added, "Without antibiotics, you have a day more fever, a day more pain, and you risk meningitis in one out of 100 patients."

In an interactive audience response session, approximately half the attendees indicated that they are already managing a small proportion of their patients with observation alone. Over two-thirds predicted that they will increase their use of the observation strategy, having the support of the new guidelines, though half believed that parents will not accept this approach for children younger than 2 years of age with what they [the parents] perceive as signs of acute otitis media. The vast majority of attendees believed that parents would, on the other hand, accept observation for children over 2 years of age with mild illness.

Dr. Marcy commented on the audience responses, "The new guidelines appear to reflect what is being done already in practice and what is slowly becoming accepted as the standard of care."

The Challenge of Multidrug Resistance: Antibiotic Selection

Rates of penicillin non-susceptible resistance of Streptococcus pneumoniae (S. pneumoniae) appear to have declined slightly from 2001 to 2002, and are clearly lower than the peak rates of 25-30% in the mid-1990s, but resistance is still a problem, exceeding 15%.⁴ Additionally, the rate of beta-lactamase-producing Haemophilus influenzae (H. influenzae) is about 25%,⁴ and even higher in some locales, and this is another component in the challenge of treating acute otitis media.

"This means a certain percentage of strains of S. pneumoniae and H. influenzae will be resistant to our treatments," stated co-chair George H. McCracken, Jr., MD, Professor of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.² Resistance is a product not only of the overuse of antibiotics but also inappropriate use of antibiotics (viral infections, insufficient coverage of primary pathogens). While antibiotic prescribing rates have decreased 25% between 1992 and 2000, "the changes in the classes of drugs we are now using is not as encouraging," observed Dr. McCracken.

Dr. McCracken went on to cite a 2003 study by McCaig et al⁵ which found that prescriptions declined 43% for amoxicillin, the preferred agent for acute otitis media and 28% for oral cephalosporins, but increased 69% for amoxicillin/clavulanate (patients <15 years), 388% for clarithromycin and azithromycin and 78% for fluoroquinolones (patients ≥15 years).

The new treatment guidelines will address resistant pneumococci by calling for higher doses of amoxicillin (90 mg/kg/day) as initial therapy given in two divided doses for 5 to 10 days. This almost doubles the serum and middle ear fluid concentrations of amoxicillin and more effectively eradicates the intermediately-resistant and highly-resistant pathogens, Dr. McCracken advised. Seventy percent of the audience indicated they are already prescribing amoxicillin at the higher dose (90 mg/kg/day).

For patients with nontype I or uncertain allergy to beta-lactam antibiotics (eg, penicillin, amoxicillin, ampicillin), the new guidelines will suggest cefdinir, cefuroxime, or cefpodoxime as safe and effective alternatives. For those patients with a history of anaphylaxis or severe allergy to beta-lactam antibiotics, macrolide- or sulfa-based antibiotic therapy is recommended.

For treatment failures or recurrent disease, high-dose amoxicillin/ clavulanate 90 mg/kg/day in two divided doses will be the preferred agent because of its coverage of resistant pneumococci and beta-lactamase-positive H. influenzae. Cefdinir, cefuroxime, cefpodoxime, or intramuscular ceftriaxone are recommended alternatives when the physician prefers not to use high-dose amoxicillin/clavulanate, Dr. McCracken stated.

Superior Palatability: Cefdinir

In a survey of attendees, the majority of clinicians indicated they treat amoxicillin failures with high-dose amoxicillin/clavulanate; for those who instead used an oral cephalosporin, cefdinir was the preferred agent among the audience.

Dr. McCracken stated as well, "Cefdinir is probably the best oral cephalosporin, based on outcomes from clinical trials, taste, tolerance, and safety. It's a good agent when you don't want to give high-dose amoxicillin/clavulanate for one reason or another, for instance, the taste of the suspension."

Dr. Marcy also emphasized the importance of prescribing an agent with an acceptable taste in order to enhance adherence and therefore clinical outcome. "It presents less of a hassle to the parents, who don't have to chase the child down to give him the medicine. It is more pleasant for the child, and taking medicine doesn't become a bad experience for him. And, it is more likely to get into the middle ear fluid and eradicate the organism, simply because the child will take it. For example, cefdinir tastes like a strawberry milkshake—it's good, while cefpodoxime and cefuroxime taste awful," remarked Dr. Marcy.

Acute Otitis Media: Expanding Treatment Options?

Antimicrobial options for treating acute otitis media may broaden in the future, but Dr. McCracken does not view this as necessarily a positive change, especially with regard to the fluoroquinolones. Although fluoroquinolones have been proposed as treatment alternatives for acute otitis media, they will not be included in the new treatment guidelines. While gatifloxacin has demonstrated a 97% rate of bacteriologic eradication of middle ear fluid pathogens, Dr. McCracken noted, "The biggest issue I see is not cartilage damage, which has not been reported to date in United States children, but the rising level of fluoroquinolone resistance worldwide—eighteen percent (18%) in Hong Kong but still less than two percent (2%) in the United States. There is a tendency for resistance to be facilitated by excessive use of fluoroquinolones in crowded conditions. Day care would be a setting where this could be a problem. These drugs should be considered to have limited purpose for treatment of acute otitis media."

Management of Pain in Acute Otitis Media

For pain associated with acute otitis media, Dr. Marcy recommended acetaminophen, non-steroidal anti-inflammatory drugs (eg, ibuprofen, naproxen), codeine-based analgesics (in selected children 18 months and older with a responsible caregiver), and myringotomy "for the screaming child with a bulging eardrum, who gets almost instant relief from this procedure." Topical analgesia (eg, benzocaine otic solution), on the other hand, is not particularly helpful, according to Dr. Marcy.

Criteria for Tympanostomy: Who, When?

"For certain types of patients, tympanostomy tubes have proven value," stated Charles D. Bluestone, MD, Eberly Professor of Pediatric Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.⁶ Indications for tympanostomy tubes include recurrent acute otitis media, chronic otitis media with effusion (3 to 4 months bilaterally or 6 months unilaterally), Eustachian tube dysfunction, atelectasis (especially at puberty), suppurative complications of otitis media, and tympanoplasty for pocket/cholesteatoma.⁷ Fortunately, delaying surgical intervention does not appear to affect developmental outcomes. In a study of 429 children with immediate versus delayed (up to 9 months) tube placement,⁸ there were no significant differences at age 3 years between the groups in speech, language, cognition, and psychosocial development, Dr. Bluestone reported.

Either prophylactic low-dose amoxicillin or tube placement will "buy the patient about a year" without infections, Dr. Bluestone advised. But currently, because of rising antimicrobial resistance, amoxicillin prophylaxis is recommended only when anesthesia is considered risky or the child is not severely affected. Dr. Bluestone administers antibiotic prophylaxis prior to tube placement because acute purulent otitis media may cause postoperative otorrhea and premature extrusion of the tympanostomy tube. Additionally, Dr. Bluestone advised culturing the middle ear effusion at the time of tube placement with symptomatic purulent effusion (eg, otalgia) or when an unusual organism may be present, as in patients with immunologic problems.

Dr. Bluestone advised clinicians to refer patients to an otolaryngologist under the following circumstances:

• Suppurative complications present or suspected (eg, mastoiditis, facial paralysis, labyrinthitis, intracranial signs and symptoms)
• Chronic perforation
• Acute otitis media unresponsive to antimicrobial treatment (ie, symptomatic treatment failure)
• Recurrent acute otitis media (eg, ≥3 episodes in 6 months or ≥4 in 12 months, with one recent episode)
• Persistent middle ear effusion post acute otitis media, >3 to 4 months
• Acute otitis media in neonates, in patients with severe otalgia, immunologically compromised patients, or seriously ill patients

Conclusion

The American Academy of Pediatrics/American Academy of Family Physicians will issue new treatment guidelines for the treatment of acute otitis media in the near future. These new guidelines will recommend high-dose amoxicillin for initial treatment, as well as cefdinir, cefuroxime axetil, or cefpodoxime for patients with uncertain history of penicillin allergy. For treatment failures, high-dose amoxicillin/clavulanate or intramuscular ceftriaxone with alternative choices of cefdinir, cefuroxime, or cefpodoxime will be recommended. For children aged 6 months and older who are not seriously ill or for whom the diagnosis of acute otitis media is uncertain, observation may be a prudent course. The new treatment guidelines give more flexibility to the clinician in the management of young children with acute otitis media.

References

1. Marcy SM. AAP/AAFP Guidelines: Observation as a Management Option. Presented as part of the CME-symposium "New Treatment Guidelines in Acute Otitis Media: An Interactive Dialogue for Practicing Clinicians" held during the American Academy of Pediatrics 2003 National Conference and Exhibition, November 3, 2003, New Orleans, Louisiana.
2. McCracken GH. The Multidrug Resistance Challenge: Selecting the Appropriate Antibiotic. Presented as part of the CME-symposium "New Treatment Guidelines in Acute Otitis Media: An Interactive Dialogue for Practicing Clinicians" held during the American Academy of Pediatrics 2003 National Conference and Exhibition, November 3, 2003, New Orleans, Louisiana.
3. Kaleida PH, Casselbrant ML, Rockette HE, et al. Amoxicillin or myringotomy or both for acute otitis media: results of a randomized clinical trial. Pediatrics. 1991;87:466-474.
4. Sader HS, et al. Diagn Microbiol Infect Dis. 2003; in press.
5. McCaig LF, Besser RE, Hughes JM. Antimicrobial drug prescription in ambulatory care settings, United States, 1992-2000. Emerg Infect Dis. 2003; 9:432-437.
6. Bluestone CD. Current Criteria for Tube Placement. Presented as part of the CME-symposium "New Treatment Guidelines in Acute Otitis Media: An Interactive Dialogue for Practicing Clinicians" held during the American Academy of Pediatrics 2003 National Conference and Exhibition, November 3, 2003, New Orleans, Louisiana.
7. Bluestone CD, Klein JO. Otitis Media in Infants and Children. ed 3. WB Saunders: 2001.
8. Paradise JL, Feldman HM, Campbell TF, et al. Effect of early or delayed insertion of tympanostomy tubes for persistent otitis media on developmental outcomes at the age of three years. N Engl J Med. 2001;344:1179-1187.

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Disclosure

Amisha Malhotra, MD
No significant relationships to disclose.

George H. McCracken Jr., MD
Grant/Research Support-Abbott Laboratories, Aventis, Bristol-Myers Squibb, Wyeth; Consultant-Abbott Laboratories, Aventis, Bristol-Myers Squibb, GlaxoSmithKline, Novartis

This report contains information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from Abbott Laboratories.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Pediatric Press Newsletter does not include discussion of treatment and indications outside of current approved labeling. This Pediatric Press Newsletter was made possible through an educational grant from Abbott Laboratories.

© 2003 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education