A Canadian perspective on the American Academy of Pediatrics guidelines for acute otitis media

In 2004, the American Academy of Pediatrics (AAP) and the American Academy of Family Physicians (AAFP) published guidelines on the management of acute otitis media (AOM) (1). These are summarized in Table 1. The guidelines contain new recommendations for both empirical and second-line antibiotic treatments; however, some of the drugs recommended are not available in Canada. What are these recommendations, and what are the options for the prescribing Canadian physician? The American Academy of Pediatrics otitis media guidelines Adapted from reference 1 The American Academy of Pediatrics otitis media guidelines Adapted from reference 1 The AAP/AAFP clinical practice guideline is a comprehensive document that covers diagnosis and management, including weighing the option of observation and symptomatic treatment, pain control, prevention measures, as well as appropriate choices for antibacterial medications. We will address the recommended antibiotics and explain why these drugs are recommended, as well as provide options for drugs that are not available in Canada. The first major new recommendation in the AAP/AAFP guidelines is an increase in the empirical treatment dose of amoxicillin. Specifically, the guidelines recommend that for most children, if an antibacterial agent is to be used, then the first-line agent to be prescribed should be amoxicillin at 80 mg/kg/day to 90 mg/kg/day. This was based on a Centers for Disease Control and Prevention (CDC) recommendation that the empirical treatment dose of amoxicillin should be increased from 40 mg/kg/day to 45 mg/kg/day, to 80 mg/kg/day to 90 mg/kg/day, owing to the rising prevalence of drug-resistant Streptococcus pneumoniae (DRSP) (2). In general, one cannot just increase the dose of a drug to overcome resistance; however, the mechanism of penicillin resistance is such that increasing the dose of amoxicillin results in serum levels that can overcome the resistance. This is based on in vitro data, not clinical trials. Penicillin susceptibility is geographically dependent, both in the United States and Canada. Thus, the CDC guidelines acknowledge that patients at very low risk for DRSP may still be treated with a regular dose of amoxicillin. This refers to patients older than two years of age, those without antibiotic exposure in the past three months and those with no daycare attendance. Moreover, since the publication of these guidelines, new data have emerged from the United States showing a change in the relative frequency of the different isolates causing AOM as a result of conjugated pneumococcal vaccine use. A significant drop (greater than 10%) in the rates of DRSP in certain communities was reported, especially in areas in which the vaccine has had universal recommendations (3); an overall decrease in the frequency of S pneumoniae isolates relative to Haemophilus influenzae (4) causing AOM was also reported. The Canadian Paediatric Society is currently revising the Canadian guidelines for first-line antibiotic treatment of AOM. In the interim, it would seem prudent to weigh all the risk factors (eg, age, daycare attendance, previous antibiotic exposure and geographical rate of drug resistance), as well as vaccination status (5) in the decision to choose high- versus standard-dose amoxicillin. It is important to remember that high-dose amoxicillin could cause diarrhea as an adverse effect. In patients with severe illness (moderate to severe ear pain and fever of 39°C or higher) and in those who fail to respond to initial management within 48 h to 72 h, the guidelines recommend the use of high-dose amoxicillin-clavulanate in two divided doses, in a 14:1 formulation (90 mg/amoxicillin component to a 6.4 mg/clavulin component). The addition of clavulanate is effective against the beta-lactamase-producing strains of H influenzae or Moraxella catarrhalis, which are thought to be the pathogens responsible for disease in those who fail initial amoxicillin treatment. Because this formulation is not available in Canada, one may prescribe the 7:1 Clavulin (GlaxoSmithKline Inc, Canada) product containing 45 mg/kg/day of the amoxicillin component and an additional amoxicillin dose of 45 mg/kg/day for a combined total of 90 mg/kg/day of amoxicillin. Clavulin-200 and -400 suspensions (7:1) are given every 12 h (6). If this treatment fails, the guidelines recommend a three-day course of parenteral ceftriaxone, owing to its superior efficacy against S pneumoniae compared with the oral antibiotics. Thus far, the recommendations can be followed through what is available in Canada. However, it is the recommended second-line agents that are more problematic. Due to potential cross-reactivity between penicillins and cephalosporins, the guidelines divide penicillin allergy into type 1 hypersensitivity reaction (urticaria or anaphylaxis) and nontype 1 reactions, and recommend the following cephalosporins for nontype 1 reactions to penicillin: cefdinir, cefpodoxime or cefuroxime axetil. However, cefdinir and cefpodoxime, oral third-generation cephalosporins, are currently not available in Canada. The use of oral third-generation cephalosporins for the treatment of AOM is based on recent evidence, which demonstrates that they have better overall clinical efficacy and antimicrobial activity than the second-generation cephalosporins (7). Both cefpodoxime and cefdinir have been shown in comparative tympanocentesis trials to have overall clinical and microbiological efficacy rates that are equivalent to those produced by amoxicillin-clavulanate. Moreover, they display longer half-lives, permitting their use as once-daily (cefdinir) and twice-daily (cefpodoxime) formulations. Finally, cefdinir has the advantage of increased palatability, with studies (8,9) showing it to have a better taste than both amoxicillin and cefprozil. This is important to increase compliance. What are the alternatives available in Canada? Cefixime is the only oral third-generation cephalosporin available in Canada. While it is active against H influenzae and M catarrhalis, it has been shown to be the least active against the pneumococci (especially DRSP) compared with all other second- and third-generation cephalosporins. It is not recommended for treatment of AOM. While the second-generation cephalosporins are, in general, less effective than the third-generation cephalosporins (2), cefuroxime axetil is the exception. The bacteriological and clinical efficacy of cefuroxime axetil has been studied in a double-tympanocentesis study (10), and has shown excellent activity against penicillin-resistant S pneumoniae, as well as beta-lactamase-producing strains of H influenzae and M catarrhalis. However, because of its poor palatability, its use as a liquid oral formulation has been limited. Cefuroxime has been judged to be so unpalatable that it compromises therapy (11). Cefprozil has a better taste and is a palatable second-generation cephalosporin. It has been shown to have limited activity against nontypable H influenzae (12); there are limited data on its effectiveness against DRSP. Cefprozil was not endorsed by the CDC in 1999 for the treatment of AOM because of the lack of evidence from clinical trials. There are some in vitro data that suggest middle-ear drug concentrations may not be high enough in DRSP infections (13), but one study (6) found it to be as effective as amoxicillin-clavulanate for the treatment of AOM. In short, the second-line alternatives for penicillin-allergic patients in Canada include cefuroxime axetil and cefprozil, but there are some limitations. What about other classes of antibiotics? Macrolide and trimethoprim-sulfamethoxazole regimens have traditionally been useful as first- and second-line agents for AOM, but they are no longer as useful. Recent Canadian pneumococ-cal surveillance data indicate that resistance to trimethoprim-sulfamethoxazole and the macrolides is substantial (approximately 20% of isolates [Canadian Bacterial Surveillance Network, personal communication]). The newer macrolides, azithromycin and clarithromycin, are slightly more effective than erythromycin, owing to improved middle-ear fluid concentrations, tissue penetration and gastrointestinal tolerability. While this group of drugs is necessary for the true type 1 penicillin-allergic patient, they are not recommended as first- or second-line treatment in the nonallergic patient. If necessary, the guidelines recommend azithromycin and clarithromycin as first-line agents. One can also use clindamycin if the infection is known or presumed to be pneumococcal. Options for the Canadian physician prescribing antibiotics for AOM to the penicillin-allergic patient are different than the AAP/AAFP recommendations owing to the difference in availability of these drugs. Cefpodoxime and cefdinir are not currently available in Canada, while cefixime, the only available third-generation cephalosporin, is not recommended for the treatment of AOM due to its poor action against S pneumoniae. The alternative second-generation drugs are cefuroxime and cefprozil. The ideal choice, therefore, will remain physician- and patient-dependant bearing these limitations in mind.

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