This report was reviewed for medical and scientific accuracy by University of Medicine and Dentistry of New Jersey.

Expert Commentary

Ron Dagan, MD, Director, Pediatric Infectious Disease Unit, Soroka University Medical Center; Professor of Pediatrics and Infectious Diseases, Ben-Gurion University of the Negev, Beer-Sheva, Israel

New guidelines on treating acute otitis media will soon be issued from the American Academy of Pediatrics/American Academy of Family Physicians that will reaffirm the safety and efficacy of high-dose amoxicillin and high-dose amoxicillin/clavulanate (Augmentin ES) in the management of infections caused by penicillin-susceptible, penicillin-intermediately-resistant, and penicillin-resistant bacteria. In a recent comparative study of acute otitis media, high-dose amoxicillin/clavulanate demonstrated superior bacteriologic efficacy in 90 to 96% of pathogens, and produced significantly more favorable clinical success rates at 12 to 14 days (end-of-therapy) than azithromycin (Zithromax).¹ Amoxicillin and amoxicillin/clavulanate, therefore, remain the mainstays of our armamentarium, including initial and recurrent infections alike, though their judicious use is only part of the proper management of acute otitis media.

Increasing bacterial resistance to antibiotic therapies is a growing global problem that threatens the utility of existing therapies and compromises patient care. The highest frequency of bacterial resistance is observed in children, especially those with acute otitis media and acute bacterial rhinosinusitis, and is generally attributed to extensive use of antibiotics and selective pressure on bacterial strains of nasopharyngeal flora. Current dogma holds that a reduction in antibiotic use will lead to a reduction in the incidence of bacterial resistance, but this approach is insufficient. The factors behind the appropriate selection of initial antibiotic therapy must also be considered. Accurate diagnosis is also critical, not only for optimal clinical outcomes but in order to reserve antibiotics for children who really need them.

This Pediatric Infectious Disease Express Report will review these important issues that were presented during a two-hour interactive CME-symposium on the management of otitis and sinusitis conducted during the American Academy of Pediatrics 2003 National Conference and Exhibition.

Introduction

According to Faculty Chair Colin D. Marchant, MD, Associate Professor of Pediatrics, Boston University School of Medicine and Tufts University School of Medicine, Director, Center for Pediatric Vaccine Research, Boston University, Boston, Massachusetts, acute otitis media and acute bacterial rhinosinusitis have similar anatomic and pathophysiologic features, are often preceded or accompanied by a viral upper respiratory infection, and have a common bacterial etiology, principally Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae), and Moraxella catarrhalis (M. catarrhalis).² Both acute otitis media and acute bacterial rhinosinusitis improve faster when treated with antibiotics than in untreated children. Upper respiratory infections without acute otitis media or acute bacterial rhinosinusitis, however, do not warrant antibiotics and their indiscriminate use result in the selection of antibiotic-resistant bacteria, side effects and unnecessary costs for the patient.

Accurate Diagnosis is Essential

The effective and responsible management of acute otitis media and acute bacterial rhinosinusitis hinges largely on proper diagnosis, which can be difficult in young children, advised Michael D. Poole, MD, PhD, Professor and Chair of Otolaryngology-Head and Neck Surgery, University of Texas Health Science Center, Houston, Texas.³ Otitis media with effusion is characterized by middle ear fluid without significant signs of inflammation. Acute otitis media, on the other hand, presents with both fluid and inflammation in the middle ear. Acute otitis media is usually symptomatic and upon examination exhibits a bulging tympanic membrane with purulent fluid, which is the sign most predictive of an infection, Dr. Poole stated.

Dr. Marchant reiterated the need for diagnostic accuracy. "Without an accurate diagnosis, the downfall of antibiotics is that we select for resistance. If we don't initiate appropriate antibacterial therapy, the result is incomplete eradication of even the susceptible bacteria. While resistance to S. pneumoniae seems to have recently stabilized, there is still ample evidence of bacterial resistance to contemplate resistant pneumococci when we select therapy," advised Dr. Marchant.

Guidelines Should Inform Treatment Decisions

Acute otitis media can be a challenge to treat due to the prevalence of penicillin-resistant S. pneumoniae (penicillin-resistant minimum inhibitory concentration (MIC) ≥2 µg/mL; intermediate-resistant MIC 0.12-1.0 µg/mL) along with beta-lactamase-producing H. influenzae and M. catarrhalis. The 28% rate of beta-lactamase production observed with H. influenzae⁴ underscores the importance of employing agents that are active against these organisms, as well as pneumococci, advised Dr. Marchant.

Bacteriologic efficacy data and to a lesser extent pharmacokinetic/pharmacodynamic data have formed the cornerstone of the current treatment guidelines for treating acute otitis media. Dr. Marchant also reviewed the current Centers for Disease Control (CDC) guidelines for the management of acute otitis media⁵ (Figure 1). The CDC guidelines state that amoxicillin is the preferred first-line agent for treating acute otitis media. In light of the increasing prevalence of drug-resistant S. pneumoniae however, for children with no antibacterial therapy within the previous 4 to 6 weeks, the guidelines recommend amoxicillin 40 to 45 mg/kg/day or 80 to 90 mg/kg/day for acute otitis media. For children with antibacterial therapy within the previous 4 to 6 weeks, the guidelines recommend amoxicillin 80 to 90 mg/kg/day, amoxicillin/clavulanate 80 to 90 mg/kg/day, or cefuroxime axetil (Ceftin).

"While these guidelines were issued in 1999, we still have resistant S. pneumoniae and H. influenzae. The guidelines are as relevant and useful today as they were then," stated Dr. Marchant.

New guidelines for the treatment of acute otitis media will be issued in early 2004 from the American Academy of Pediatrics/American Academy of Family Physicians. These guidelines will recommend initial therapy with high-dose amoxicillin or high-dose amoxicillin-clavulanate. In his presentation, Dr. Poole commented that he is increasingly initiating therapy for acute otitis media with high-dose amoxicillin (80 to 90 mg/kg/day) twice a day and sees "little rationale for using historical doses now."

In contrast, Dr. Poole prescribes antibiotics for sinusitis when the patient is not better after 10 days or the patient's symptoms (eg, nasal discharge, cough) worsen after 5 to 7 days. Systemic signs and symptoms (eg, fever, sore throat) need not be present and are likely to indicate another condition, Dr. Poole advised. The American Academy of Pediatrics clinical practice guidelines for the management of sinusitis recommends amoxicillin 45 or 90 mg/kg/day in two divided doses for mild to moderate infection.⁶ For those patients with amoxicillin allergy, either cefuroxime axetil 30 mg/kg/day, cefdinir (Omnicef) 14 mg/kg/day, or cefpodoxime (Vantin) 10 mg/kg/day are appropriate alternatives. In the case of patient history of anaphylaxis, selection of a non-penicillin, non-cephalosporin antibiotic is recommended.

Dr. Poole noted that the antimicrobial treatment guidelines for acute bacterial rhinosinusitis issued by the Sinus & Allergy Health Partnership are somewhat more detailed, taking into consideration past antibiotic use, severity of sinusitis, and drug allergies.⁷ In each treatment guideline, amoxicillin is the recommended initial treatment option for acute bacterial rhinosinusitis.

Treatment Failures versus New Infections

In spite of effective therapy, treatment failures can occur. Dr. Poole expressed that treatment failures are less common than clinicians and parents believe and not common at all with agents that produce high bacterial cure rates. Symptoms of a new infection arising soon after the completion of guideline-based antibiotic therapy are likely to represent new infections, not treatment failures, Dr. Poole advised. New organisms are usually responsible even for clinical recurrences within the first week, and are nearly always the cause of episodes occurring greater than three weeks after treatment. Leibovitz et al showed that new infections were the cause of clinical recurrences 36% of the time between Days 1 to 7, 35% between Days 8 to 14, 19% between Days 15 to 21, and 9% between Days 22 to 28⁸ (Figure 2). In other words, for infections recurring within 28 days of the initial infection, 89% were caused by a new pathogen. Mild recurrences may not be infections at all, Dr. Poole added.

"This has real implications in clinical practice," observed Dr. Poole. "We all have patients who have finished their antibiotic therapy only to develop another infection in less than a month. The family says the antibiotic didn't work and they don't want treatment with more amoxicillin. You have to explain to them that their child did respond to the antibiotic therapy, and that this is a new infection. If you move away from amoxicillin or amoxicillin/clavulanate, you are often going to have less effective treatment."

Evidence-based Antibiotic Selection

Ron Dagan, MD, Director of the Pediatric Infectious Disease Unit, Soroka University Medical Center, and Professor of Pediatrics and Infectious Diseases, Ben-Gurion University of the Negev, Beer-Sheva, Israel,⁹ discussed evidence-based antibiotic selection, cautioning clinicians to "critically judge the data before you accept them as evidence."

A common assumption by many clinicians is that after a true treatment failure with amoxicillin, vis-а-vis actual bacteriologic relapses as illustrated in Figure 2, the appropriate second-line agent should be an antibiotic drug from a different class of antibiotic—a macrolide, in particular azithromycin, or an oral cephalosporin. Dr. Dagan strongly disagrees with this approach, and presented data suggesting these alternative treatment options are inadequate against organisms that are penicillin-resistant or intermediately-resistant to penicillin—bacteria that frequently cause treatment failures in acute otitis media.

Data from the SENTRY Antimicrobial Surveillance Program (1997-2001) showed that 65.3% of pneumococci that were penicillin-resistant were also fully-resistant to macrolides and 35.3% of those intermediately-resistant to penicillin displayed full resistance to macrolides.¹⁰ Furthermore, antibiotic penetration to the site of infection affects bacteriologic efficacy. While azithromycin has excellent intracellular penetration, the organisms causing acute otitis media are primarily extracellular, Dr. Dagan pointed out. This results in very low extracellular azithromycin concentrations, thus lending to successful treatment against only bacteria with very low MIC.

According to Dr. Dagan, azithromycin is only effective against pneumococci that are macrolide-susceptible. "And these are not the organisms found in treatment failures with amoxicillin," stated Dr. Dagan. The pathogens most likely to persist after bacteriologic failure with high-dose amoxicillin are beta-lactamase-producing H. influenzae,^[11] against which azithromycin produces bacteriologic failure rates^[12,13] comparable to placebo,^[14] Dr. Dagan noted. In an analysis evaluating antibiotic therapy for acute otitis media, azithromycin failed to eradicate H. influenzae in over 60% of cases as determined by a second tympanocentesis on Days 2 to 6 of treatment.¹⁵

While parenteral ceftriaxone may be an effective second-line therapy for acute otitis media, oral cephalosporins provide, like azithromycin, no clinical benefit in fully-resistant pneumococcal strains and little activity against intermediately-resistant strains, Dr. Dagan added. Furthermore, the ability to eradicate H. influenzae from middle ear fluid is limited.

High-dose amoxicillin, however, as determined by pharmacokinetic/pharmacodynamic breakpoints, is effective against 100% of susceptible pneumococcal isolates, 100% of intermediately-resistant isolates, and 87% of fully-resistant isolates (Alexander Project 1999-2000^[16] as analyzed by lead author Michael R. Jacobs, MD⁹). Similarly, Dr. Dagan noted, high-dose amoxicillin/clavulanate yields a high (96%) overall bacteriologic eradication rate: 99% for pneumococci, 90% for H. influenzae, 97% for mixed pneumococci and H. influenzae, and 100% for M. catarrhalis and Group A streptococci.¹⁷

While differences between antibiotic agents may seem small, Dr. Dagan said the minimal differences are especially significant from a societal perspective. It is estimated that 24 million episodes of acute otitis media occur yearly in the United States.¹⁸ An antibiotic that is just 5 to 10% less effective can translate into 1 to 2.5 million more treatment failures per year, Dr. Dagan proffered.

Dr. Dagan reminded meeting attendants that it was important to remember, especially in evaluating clinical trial data, that nearly 20% of S. pneumoniae and 50% of H. influenzae will be eradicated even without antibiotic therapy.¹⁴ "If you give an antibiotic to a child and the child improves, this does not necessarily mean the antibiotic is working," commented Dr. Dagan, noting that spontaneous clinical cure rates are quite high^[15] but acknowledging that antibiotics do shorten the duration of illness. Continuing, Dr. Dagan stated, "Placebo works well in most patients, and we use many antibiotics today that have antibacterial activity comparable to placebo against some of the main pathogens."

New, Comparative Study of High-dose Amoxicillin/Clavulanate versus Azithromycin in Acute Otitis Media

Recently, a large multicenter study of 731 young children (median age 14 months, 86% <24 months) with stringently diagnosed acute otitis media (double tympanocentesis) demonstrated that clinical and bacteriologic outcomes were significantly more favorable with high-dose amoxicillin/clavulanate than azithromycin.¹ The children were randomized to high-dose amoxicillin/clavulanate (n = 368; 90/6.4 mg/kg/day twice daily for 10 days) or azithromycin (n = 363; 10 mg/kg Day 1, 5 mg/kg/day, Days 2 to 5) and evaluated at on-therapy (Days 4 to 6), end-of-therapy (Days 12 to 14), and follow-up (Days 21 to 25) visits. Bacteriologic eradication results were available for 89% (242/271) of children.

In evaluable children, the proportion showing clinical cure or improvement at on-therapy, end-of-therapy, and follow-up was significantly greater with high-dose amoxicillin/clavulanate than with azithromycin (95% vs 88%, 91% vs 81%, and 80% vs 71%, respectively; P<.05 for each comparison). Selected outcomes are illustrated in Figure 3. Acute otitis media pathogens were eradicated on-therapy in 94% of high-dose amoxicillin/clavulanate-treated children compared with 65% of azithromycin-treated children (P<.001).

Azithromycin resistance was noted in 51% of penicillin-resistant (MIC ≥2 µg/mL), 17% of penicillin-intermediately-resistant, and 4% of penicillin-susceptible S. pneumoniae isolates. Penicillin-resistant S. pneumoniae was eradicated from 92% of children on high-dose amoxicillin/clavulanate versus 55% on azithromycin (P<.01).

Commenting on the findings, Dr. Dagan concluded, "Clearly, we see that high-dose amoxicillin/clavulanate is superior to azithromycin for acute otitis media. H. influenzae was the predominant reason why azithromycin did not work well in these children."

Conclusion

Antimicrobial resistance to S. pneumoniae and the prevalence of beta-lactamase-producing organisms (H. influenzae) have greatly challenged clinicians treating acute otitis media and acute bacterial rhinosinusitis. Although reductions in the use of antibiotics are helpful with respect to bacterial resistance, just as important is the appropriate selection of initial antibiotic therapy to effectively cover the majority of causative pathogens for these conditions. Historically, amoxicillin and amoxicillin/clavulanate have been the preferred agents in treating acute otitis media and acute bacterial rhinosinusitis. The new treatment guidelines for acute otitis media are forthcoming and will recommend high-dose amoxicillin and high-dose amoxicillin/clavulanate as the preferred treatment options.

References

1. Hoberman A, Dagan R, Rosenblut A, Leibovitz E, Huff A, Wynne B. Extra-strength amoxicillin-clavulanate (A/C-ES) vs azithromycin (AZI) for acute otitis media (AOM) in children. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 14-17, 2003, Chicago, Illinois. Abstract G-459.
2. Marchant CD. New Data, New Guidelines: Management of Otitis and Sinusitis in Children. Presented as part of the CME-symposium "New Data, New Guidelines: Management of Otitis and Sinusitis in Children" held during the American Academy of Pediatrics 2003 National Conference and Exhibition, November 1, 2003, New Orleans, Louisiana.
3. Poole MD. Otitis Media and Sinusitis Diagnosis and Response to Therapy. Presented as part of the CME-symposium "New Data, New Guidelines: Management of Otitis and Sinusitis in Children" held during the American Academy of Pediatrics 2003 National Conference and Exhibition, November 1, 2003, New Orleans, Louisiana.
4. Jacobs MR. Pediatr Infect Dis. 2003, in press.
5. 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.
6. Clinical practice guideline: management of sinusitis. American Academy of Pediatrics. Subcommittee on Management of Sinusitis and Committee on Quality Improvement. Pediatrics. 2001;108:798-808.
7. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Sinus & Allergy Health Partnership. Otolaryngol Head Neck Surg. 2000;123(1 Pt 2):1-31.
8. Leibovitz E, Greenberg D, Piglansky L, et al. Recurrent acute otitis media occurring within one month from completion of antibiotic therapy: relationship to the original pathogen. Pediatr Infect Dis J. 2003;22:209-216.
9. Dagan R. What is the Evidence for Evidence-based Medicine in Acute Otitis Media? Presented as part of the CME-symposium "New Data, New Guidelines: Management of Otitis and Sinusitis in Children" held during the American Academy of Pediatrics 2003 National Conference and Exhibition, November 1, 2003, New Orleans, Louisiana.
10. Jones RN, Mutnick AH, Varnam DJ. Impact of modified nonmeningeal Streptococcus pneumoniae interpretive criteria (NCCLS M100-S12) on the susceptibility patterns of five parenteral cephalosporins: report from the SENTRY antimicrobial surveillance program (1997 to 2001). J Clin Microbiol. 2002;40:4332-4333.
11. Piglansky L, Leibovitz E, Raiz S, et al. Bacteriologic and clinical efficacy of high dose amoxicillin for therapy of acute otitis media in children. Pediatr Infect Dis J. 2003;22:405-413.
12. Dagan R, Johnson CE, McLinn S, et al. Bacteriologic and clinical efficacy of amoxicillin/clavulanate vs azithromycin in acute otitis media. Pediatr Infect Dis J. 2000;19:95-104.
13. Dagan R, Leibovitz E, Fliss DM, et al. Bacteriologic efficacies of oral azithromycin and oral cefaclor in treatment of acute otitis media in infants and young children. Antimicrob Agents Chemother. 2000;44:43-50.
14. Howie VM, Ploussard JH. Efficacy of fixed combination antibiotics versus separate components in otitis media. Effectiveness of erythromycin estolate, triple sulfonamide, ampicillin, erythromycin estolate-triple sulfonamide, and placebo in 280 patients with acute otitis media under two and one-half years of age. Clin Pediatr (Phila). 1972;11:205-214.
15. Dagan R, Leibovitz E. Bacterial eradication in the treatment of otitis media. Lancet Infect Dis. 2002;2:593-604.
16. Jacobs MR, Felmingham D, Appelbaum PC, Gruneberg RN for The Alexander Project Group. The Alexander Project 1998-2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection to commonly used antimicrobial agents. J Antimicrob Chemother. 2003;52:229-246.
17. Dagan R, Hoberman A, Johnson C, et al. Bacteriologic and clinical efficacy of high dose amoxicillin/clavulanate in children with acute otitis media. Pediatr Infect Dis J. 2001;20:829-837.
18. Schappert SM. Office visits for otitis media: United States, 1975-90. Adv Data. 1992;214:1-19.

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Disclosure

Ron Dagan, MD
Consultant-Abbott, Aventis/Aventis Pasteur, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Schering-Plough;
Grant/Research Support-Abbott, Aventis/Aventis Pasteur, Bayer, Biotechnology General, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Marion-Merrell-Dow, Merck & Co., Inc., Pfizer Inc., Roche Laboratories, Schering-Plough, Wyeth-Lederle Vaccines & Pediatrics, Zeneca

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 GlaxoSmithKline.

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 Infectious Disease Express Report™ includes discussion of treatment and indications outside of current approved labeling. This Pediatric Infectious Disease Express Report™ was made possible through an educational grant from GlaxoSmithKline.

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