High dose amoxicillin: Rationale for use in otitis media treatment failures

A small number of effective therapeutic options exist for children with acute otitis media who fail to respond to initial therapy or whose illness relapses quickly after discontinuing antibiotics (1). One option is the use of high dose (90 to 100 mg/kg/day) oral amoxicillin. This paper discusses the rationale for this choice in the above clinical circumstances.

Children may fail initial therapy for a variety of reasons. However, recent evidence points to infection with resistant strains of Streptococcus pneumoniae as the most significant reason for failure in compliant patients (2). Penicillin resistance among strains of S pneumoniae may be either intermediate or high level. Strains with a penicillin minimal inhibitory concentration (MIC) less than 0.1 μg/mL are classified as susceptible to penicillin, those with a MIC greater than 0.1 μg/mL but less than or equal to 1.0 μg/mL are considered to have intermediate resistance, while those with a MIC greater than 1.0 μg/mL are considered to have high level resistance. Usually, isolates with high level resistance have MICs of 2 or 4 μg/mL. Isolates with MICs of 8 μg/mL or greater are rarely observed. Between 10% to 20% of isolates in Canada submitted to the National Centre for Streptococcus are resistant to penicillin, with 1.8% of the isolates having a MIC of 2 μg/mL or greater (3,4).

Strains of S pneumoniae with both intermediate and high level penicillin resistance are more commonly isolated from children who fail initial therapy or who received antibiotics recently (within the previous two to four weeks) (1,2). Therefore, in situations when the signs and symptoms of otitis media (ie, fever, pain or purulent effusion) fail to resolve or when there is an early recurrence of this illness, the antibiotic chosen must be effective against at least intermediate penicillin-resistant S pneumoniae infection of the middle ear fluid. Preferably, the antibiotic should also be effective against most high level penicillin-resistant S pneumoniae strains.

To effect a cure reliably, the concentration of an antibiotic in an infected site must reach and exceed the antibiotic MIC for the organism. Amoxicillin does not demonstrate increased killing efficacy against S pneumoniae with antibiotic levels higher than the MIC (5). However, generally, antibiotic peak concentrations reaching at least four times the MIC of the antibiotic for the organism are preferred in case there are undetected bacterial subpopulations whose MICs are one- to twofold higher than the measured MIC. An antibiotic concentration four times greater than the reported MIC ensures that the antibiotic level will be sufficient should these relatively more resistant strains be present in significant numbers.

Amoxicillin generally penetrates the middle ear fluid well; in doses of 40 to 50 mg/kg/day, it usually exceeds the MIC of sensitive organisms and frequently exceeds the MICs of intermediate-resistant organisms. Studies involving children with acute or chronic ear infections have found that following single doses of 13 to 15 mg/kg of amoxicilin, the mean concentration of the drug in the middle ear ranged from 2.8 to 5.6 μg/mL (5–9). Two studies have addressed the concentrations achieved in the middle ear following administration of higher doses of amoxicillin. In both studies, patients tolerated the higher dosage of amoxicillin without any significant increase in side effects including diarrhea. Harrison and Welch (10) studied amoxicillin levels in the middle ear following the administration of a single oral 30 mg/kg dose. The mean middle ear amoxicillin levels, measured 100 to 150 mins after the antibiotic was taken, were 4.34±2.05 μg/mL. Only one child had middle ear fluid levels below 2 μg/mL, while fluid levels in the other children were substantially higher. Seikel et al (11) studied higher doses of amoxicillin-clavulanate (35 to 45 mg/kg/dose) in 20 children. Middle ear amoxicillin levels measured 1 to 3 h after administration were greater than 1 μg/mL in 18 children, and greater than 4 μg/mL in eight children. The high degree of variability in the antibiotic levels in the middle ear in all of these studies reflects the variable populations and study protocols used. Despite this, the reported data show that high doses of amoxicillin, with or without clavulanate, will generally achieve levels in the middle ear fluid that exceed the MICs of all intermediate and most high level penicillin-resistant S pneumoniae (12,13).

However, the time that the concentration of the antibiotic exceeds the MIC in the middle ear fluid is another significant factor related to the effectiveness of an antibiotic for otitis media. The regrowth of organisms not killed initially occurs rapidly once the antibiotic concentration falls below the MIC. For most antibiotics, maximal killing is observed when the antibiotic levels exceed the MIC for more than 60% of the dosing interval. However, because of the relationship between amoxicillin and S pneumoniae, maximal killing is reliably observed when the antibiotic’s levels exceed the MIC for as little as 30% of the time (5). The time that the antibiotic levels remain above the MIC in the middle ear fluid has not been determined directly. This can be estimated based on calculations using ratio of the antibiotic levels obtained in the middle ear relative to simultaneous serum levels combined with studies directly measuring the changes in antibiotic serum levels over time. As well, Craig and Andes (5) speculated that the ratio of the antibiotic level obtained in the middle ear fluid to the MIC of the organism reflects the percentage of the dosage interval that antibiotic levels in the middle ear fluid are above the MIC. Based on their calculations, amoxicillin (at a 13.3 mg/kg dose) was the only orally available drug regime studied that could exceed the MICs of intermediate and some high level penicillin-resistant S pneumoniae for 40% or more of the dosing interval. Extrapolating from their calculations, 30 to 45 mg dosing of amoxicillin results in adequate duration for effectiveness of coverage in most instances of S pneumoniae isolates with MICs less than or equal to 4 μg/mL (12).

Oral amoxicillin at doses of 90 to 100 mg/kg/day given tid for 10 days should be considered as the first-line oral therapy for otitis media in children who recently (within the past month) completed therapy for a previous episode of otitis media or failed to respond (ie, persistent fever, pain and middle ear fluid that appeared purulent) to initial therapy. If the addition of clavulanate is preferred, patients can be given prescriptions for 45 mg/kg/day of amoxicillin-clavulanate given bid or tid, combined with the simultaneous tid administration of 50 mg/kg/day of amoxicillin. This prevents additional anticipated side effects in relation to the higher dose of clavulanate, if 90 mg/kg/day of the traditional combination of amoxicillin-clavulanate were used. The other alternative is ceftriaxone sodium (50 mg/kg/day) administered intramuscularly or intravenously for one to three days. This regime is the only alternative that has been studied and shown to be effective in these situations (5,14,15). Successful treatment with the macrolide antibiotics (erythromycin, azythromycin or clarithromycin) in these situations will depend on the frequency of resistance to this class of antibiotics among S pneumoniae strains in the community. It is possible that the use of higher doses of other oral antibiotics approved for the treatment of otitis media may also be effective. However, no studies have documented the effectiveness of their use against penicillin-resistant S pneumoniae in this manner, and their costs are higher compared with that of high dose amoxicillin.