This report was reviewed for medical and scientific accuracy by Amisha Malhotra, MD, Assistant 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

Appropriate antibiotic treatment of acute otitis media is essential for successful patient outcomes and the prevention of antibiotic resistance. Concern over the latter is evidenced by prescribing trends—decreased use of standard antibiotic therapies (amoxicillin) and increased use of expensive, broader-spectrum antibiotic agents for initial therapy. Evidence from poorly designed clinical trials and meta-analyses have likely contributed to the misconception that standard antibiotic therapies are only modestly effective in treating acute otitis media and the greater acceptance of "watchful waiting" or delayed treatment in patients with acute otitis media, especially those younger than 2 years of age.

Current treatment guidelines suggest that standard therapies remain effective in patients who truly have acute otitis media. They emphasize the importance of accurate diagnosis, including the differentiation of acute otitis media, a condition that is likely to respond to antibiotic therapy, and otitis media with effusion, a condition that is not. Unlike "watchful waiting", this approach prevents unnecessary antibiotic prescribing while allowing timely treatment of patients who have underlying bacterial infections. Furthermore, these guidelines recommend reservation of broader-spectrum antibiotic agents for patients who cannot tolerate or who do not respond to first-line therapy, thus minimizing the risk for the development of resistance to these agents while assuring success to treatment with broader-spectrum antibiotics (eg, amoxicillin-clavulanate).

The introduction of pneumococcal conjugate vaccine may further help preserve the efficacy of standard antibiotic therapies for acute otitis media. While the overall effect on pneumococcal conjugate vaccine on the incidence of acute otitis media is modest at best, its use may result in a shift in bacterial etiology; possibly from high-level resistant strains of Streptococcus pneumoniae (S. pneumoniae) to the more antibiotic-susceptible pneumococci and to Haemophilus influenzae (H. influenzae). Additional data are required to validate this notion.

Standard antibiotic therapies maintain an important role in the management of acute otitis media. Judicious use of these antibiotic therapies in patients with acute otitis media, as well as in patients with other bacterial infections, should help preserve their effectiveness and clinical utility.

Perspective

Acute otitis media is a common pediatric diagnosis—approximately three-fourths of all children in the United States will have experienced at least one episode of acute otitis media by the time they reach 3 years of age.¹ For years, amoxicillin was generally accepted by physicians as the standard therapy for acute otitis media. However, concerns over antibiotic overuse and the development of antibiotic resistance have resulted in changes in the way physicians diagnose and treat acute otitis media. Several recent studies have analyzed these changing prescribing patterns and raised important concerns regarding the impact of these changes on clinical outcomes.

Changing Patterns of Antibiotic Use in Clinical Practice

Appropriate antibiotic use is essential to slow the development of antibiotic resistance. Evidence-based guidelines from the Centers for Disease Control and Prevention (CDC)^2,3 and Institute for Clinical Systems Improvement (ICSI)⁴ recommend amoxicillin as first-line therapy for acute otitis media (Table 1). According to the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group, amoxicillin is first-line therapy in either regular or a high-dosage regimen because it is "highly effective against pneumococci and displays the best pharmacodynamic profile (longest time above MIC₉₀) against drug-resistant S. pneumoniae. In addition to excellent pharmacokinetic and pharmacodynamic properties, amoxicillin has a long record of safety and clinical efficacy in treating otitis media, has a narrower spectrum of activity than many of the alternative agents, and is inexpensive."³

Recommended dosages and duration of treatment depend on certain patient characteristics, such as age (eg, patients <2 years should be treated with full 10-day courses of therapy because studies have not proven the efficacy of shorter courses in this population); risk for infection with drug-resistant S. pneumoniae (eg, previous recent antibiotic exposure or daycare attendance); and risk for treatment failure (eg, patients with underlying medical conditions or chronic or recurrent otitis media).

Recent evidence suggests that amoxicillin is no longer being consistently used as first-line acute otitis media therapy. A review of drug utilization patterns for otitis media from a preferred provider organization over a 3-year period illustrated this decline.⁵ In this analysis, amoxicillin was prescribed for only 31% of 6997 acute otitis media cases and 19% of 269 recurrent cases. A wide variety of other antibiotics were prescribed for the remainder of patients (Figure 1). Furthermore, duration of treatment varied. Eighty-two percent of acute otitis media in children ≤2 years was prescribed the recommended 10-day course of amoxicillin therapy, and 18% of recurrent otitis media in children ≤2 years was prescribed the recommended 14 or more days of therapy with amoxicillin. For persons >2 years, 8% of acute otitis media was prescribed the recommended 5 to 7 day duration of therapy of amoxicillin, and 7% of recurrent otitis media was prescribed the recommended 14 or more days of therapy with amoxicillin. Many physician specialties were represented in this study; however, general/family practice physicians treated the majority of patients (47%).

In the ambulatory care setting, antibiotic prescribing patterns are changing as well, likely a result of efforts to curb antibiotic overuse and combat the development of antibiotic resistance. A recent secondary data analysis using the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey demonstrated significant changes in ambulatory prescribing patterns over the last decade.⁶ Between 1992 and 2000, the population- and visit-based antibiotic prescribing rates decreased significantly by 23% and 25%, respectively (both P<.001), driven largely by a decrease in prescribing by office-based physicians. During this same time, visit-based antibiotic prescribing decreased 33% (P<.001) and 34% (P<.001) among pediatricians and general/family practice physicians, respectively. For children (<15 years of age) prescribing rates declined 34% (P<.001) in physicians' offices and 13% (P<.001) in emergency departments. The physician's office was the only ambulatory setting which experienced a decline in antibiotic prescribing rates for persons ≥15 years (-24%; P<.001), while an increasing trend was seen in outpatient departments (+35%; P = .002), and no change was reported in emergency departments.

During the study period, the prescribing rates for amoxicillin and ampicillin, cephalosporins, and erythromycin declined significantly (-43%, -28%, and -76%, respectively; P<.001 for all), while the prescribing rates for azithromycin and clarithromycin, quinolones (among patients ≥15 years of age), and amoxicillin/clavulanate potassium (among patients <15 years of age) increased significantly (+388%, +78%, and +69%; P<.001 for all) (Figure 2). Comparison of these findings demonstrates a disturbing trend—the increasing ambulatory use of newer, more-expensive, broad-spectrum antimicrobials. While clarithromycin and azithromycin have been recommended for community-acquired pneumonia,⁷ this is unlikely to account for the dramatic increase in their use. Moreover, fluoroquinolones, in addition to clarithromycin and azithromycin, are rarely indicated as first-line therapy for other respiratory infections.^8,9 This is alarming in light of adverse events associated with fluoroquinolone use—neuropsychiatric, cutaneous, tendon and cardiac involvement.¹⁰ The increasing use of these agents warrants concern in light of the rise in macrolide- and fluoroquinolone-resistant pneumococci in many parts of the world.^11-16

While this study did not specifically study antibiotic use in otitis media, it seems likely that data from children in this study are largely derived from children with otitis media, as otitis media is the most common reason for prescribing antibiotics in children.^17,18

Differentiating Acute Otitis Media and Otitis Media with Effusion

Judicious antibiotic use begins with appropriate diagnosis. Young patients with acute otitis media are likely to benefit from antibiotic therapy, which treats the underlying bacterial infection. However, many patients with symptoms suggestive of acute otitis media have otitis media with effusion, a condition in which the middle ear effusion is usually sterile. Antibiotic use in these patients is inappropriate and may contribute to the development of antibiotic resistance.¹⁹

Inclusion of patients with otitis media with effusion in antibiotic clinical trials has likely resulted in the underestimation of antibiotic efficacy and contributed to the acceptance of "watchful waiting", especially in those ≤2 years of age.²⁰ Improved diagnoses could also minimize unnecessary antibiotic use (patients with otitis media with effusion) and prevent treatment delays in patients with true acute otitis media. CDC guidelines recommend that a diagnosis of acute otitis media should include both documented middle ear effusion and signs or symptoms of acute local or systemic illness.² Differential diagnosis of acute otitis media and otitis media with effusion can be further improved by requiring that definite abnormalities of tympanic membrane indicative of acute inflammation (bulging or fullness without bulging plus marked discoloration [hemorrhagic, white, or yellow] be present²¹ (Table 2). Of these, bulging of the membrane is most indicative of acute otitis media.

Impact of Pneumococcal Conjugate Vaccine

The introduction of conjugated pneumococcal vaccine has been shown to provide modest protection against otitis media (7.8% reduction in office visits over a 3.5-year period 95% Confidence Interval (CI), 5.4-10.2%; 10% reduction in the risk of 3 visits/6 months and 26% reduction in 10 visits per 6 months).²² Conjugated pneumococcal vaccine also reduced the frequency of tube placements (24%; 95% CI, 12-35%). Whereas consistent use of conjugated pneumococcal vaccine may possibly reduce infections caused by the most resistant strains of S. pneumoniae, it may also cause a shift in bacterial etiology of otitis media to fewer resistant pneumococci and more H. influenzae. Therefore, empiric otitis media therapies should demonstrate adequate activity against these organisms.³

Conclusion

Current evidence supports the use of antibiotics to treat acute otitis media in children less than 2 years of age. Careful diagnosis can prevent inappropriate antibiotic use (ie, in patients with otitis media with effusion) and is a more desirable approach than "watchful waiting" in this age group. The increasing use of pneumococcal conjugate vaccine may result in fewer highly resistant pneumococci and more H. influenzae causing acute otitis media, but additional data are required to confirm this hypothesis.

References

1. Acute otitis media. Roche Laboratories, Inc. Total Res Utilization Conspectus. 1999;1:1-56.
2. Dowell SF, Marcy MS, Phillips WR, Gerber MA, Schwartz B. Otitis media-principles of judicious use of antimicrobial agents. Pediatrics. 1998; 101:165-171.
3. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance - a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J. 1999;18:1-9.
4. Health care guideline: diagnosis and treatment of otitis media in children. 2002. Institute for Clinical Systems Improvement. Available at http://www.icsi.org/index.asp. Accessed June 13, 2003.
5. McEwen LN, Farjo R, Foxman B. Antibiotic prescribing for otitis media: how well does it match published guidelines? Pharmacoepidemiol Drug Saf. 2003; 12:213-219.
6. McCaig LF, Besser RE, Hughes JM. Antimicrobial drug prescriptions in ambulatory care settings, United States, 1992-2000. Emerg Infect Dis. 2003; 9:432-437.
7. Bartlett JG, Dowell SF, Mandell LA, File TM, Musher DM, Fine MJ. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis. 2000;31:347-382.
8. Gonzales R, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for treatment of acute respiratory infections in adults: background, specific aims, and methods. Ann Intern Med. 2001;134:479-486.
9. Hickner JM, Bartlett JG, Besser RE, Gonzales R, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background. Ann Intern Med. 2001;134:498-505.
10. Fluoroquinolones in ambulatory ENT and respiratory tract infections: rarely appropriate. Prescrire Int. 2003;12:26-27.
11. Whitney CG, Farley MM, Hadler J, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med. 2000;343:1917-1924.
12. Hyde TB, Gay K, Stephens DS, et al. Macrolide resistance among invasive Streptococcus pneumoniae isolates. JAMA. 2001:286;1857-1862.
13. Ho PL, Yung RW, Tsang DN, et al. Increasing resistance of Streptococcus pneumoniae to fluoroquinolones: results of a Hong Kong multicentre study in 2000. J Antimicrob Chemother. 2001;48:659-665.
14. Gay K, Baughman W, Miller Y, et al. The emergence of Streptococcus pneumoniae resistant to macrolide antimicrobial agents: a 6-year population-based assessment. J Infect Dis. 2000;182:1417-1424.
15. Chen DK, McGeer A, de Azavedo JC, Low DE. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada: Canadian Bacterial Surveillance Network. N Engl J Med. 1999;341:233-239.
16. Granizo JJ, Aguilar L, Casal J, Garcia-Rey C, Dal-Re R, Baquero F. Streptococcus pneumoniae resistance to erythromycin and penicillin in relation to macrolide and beta-lactam consumption in Spain (1979-1997). J Antimicrob Chemother. 2000;46:767-773.
17. Pelton SI. Clinical management of respiratory infections: healthcare decisions in an age of increasing pathogen resistance. Challenges in the Management of Otitis Media. Am J Manag Care. 1999;5(suppl I):S662-S669.
18. Berman S, Byrns PJ, Bondy J, Smith PJ, Lezotte D. Otitis media-related antibiotic prescribing patterns, outcomes, and expenditures in a pediatric medicaid population. Pediatrics. 1997;100:585-592.
19. File TM, Hadley JA. Rational use of antibiotics to treat respiratory tract infections. Am J Manag Care. 2002;8:713-727.
20. Wald ER. Acute otitis media: more trouble with the evidence. Pediatr Infect Dis J. 2003;22:103-104.
21. Pichichero ME. Acute otitis media: Part I. Improving diagnostic accuracy. Am Fam Physician. 2000;61:2051-2056.
22. Fireman B, Black SB, Shinefield HR, Lee J, Lewis E, Ray P. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J. 2003; 22:10-16.

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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 no 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