Amoxicillin treatment of AOM: confessions from a nonconformist

February 2002

After the emergence and widespread distribution of penicillin-resistant Streptococcus pneumoniae, a group of pediatric infectious disease specialists, recognized experts in the management of acute otitis media (AOM), stated that in areas of the country where there is a high rate (>20%) of penicillin resistance, the dose of amoxicillin should be doubled from 40-50 mg/kg/day to 80-90 mg/kg/day. Many other pediatric infectious disease specialists and academic pediatricians fell in line with this recommendation and soon many generalist pediatricians, pediatric residents and emergency medicine physicians complied.

The rationale for this recommendation was that pneumococcal resistance to penicillin and amoxicillin was based on a genetic alteration of a penicillin-binding protein on its cell wall. Increasing the level of penicillin in blood or middle ear exudates overcomes intermediate levels of resistance (0.1 µg/ml to 2.0 µg/ml) of S. pneumoniae to amoxicillin but usually cannot overcome high levels of resistance (>2.0 µg/ml). There has been no published study that compared in a head-to-head design, the lower dose of amoxicillin with the high-dose amoxicillin. The recommendation was made based on pharmacodynamics principles.

Resistance

Resistance of Haemophilus influenzae and Moraxella catarrhalis to amoxicillin is due to production of ß-lactamase enzymes. This method of antibiotic resistance does not change with a doubling or tripling of the dose of amoxicillin because the ß-lactamase molecule produced by these gram-negative organisms irreversibly binds to the amoxicillin molecule.

I practice in an area of the country in which >20% of S. pneumoniae isolated from cultures of the blood or middle ear are penicillin and amoxicillin resistant. Nevertheless, I am one of the few practicing pediatricians in my area that resisted the recommendation to prescribe a high dose of amoxicillin for AOM in children. Two years after the recommendation to “double the dose” was made, I continue to prescribe amoxicillin 50 mg/kg/day in two divided doses. I have not noticed any increase in cases of persistent or rapidly relapsing AOM in my pediatric practice.

Because I participate in clinical trials of antibiotics for AOM, I currently perform at least 50 tympanocentesis procedures per year. Most of these procedures have been on children who met criteria for “difficult to treat” and about one-third of them had failed to improve on amoxicillin treatment for AOM. Ninety percent of these middle ear exudate cultures grew bacterial pathogens. We continue to recover the expected 40% S. pneumoniae species from our middle-ear cultures. Of these, 75% are penicillin susceptible and 25% are penicillin resistant. One of three isolates of penicillin-resistant S. pneumoniae, or eight of 100 cases of AOM demonstrate high-level (absolute) resistance that would not be killed by doubling or tripling the dose of amoxicillin. This means that in my area there is a theoretical chance of about 7% of young children with AOM that the 80-90 mg/kg dose of amoxicillin would have been helpful to cure middle ear infections caused by S. pneumoniae with intermediate level resistance to penicillin (amoxicillin).

We have learned that resistance to penicillin does not mean that those “bugs” produce more severe infections in the middle ear. The height of fever and the degree of pain seem to be indistinguishable on the basis of resistance to antibiotics. And if resistance is so worrisome, why don’t we skip over amoxicillin as a therapeutic choice and choose a more broad-spectrum antibiotic? The two so-called lightweights of the big three bacterial species (H. influenzae and M. catarrhalis) causing approximately 40% of all cases of AOM in young children have very high ß-lactamase mediated amoxicillin-resistance rates (50% and 95%, respectively). We know that they too can cause pain and fever reference. Yet, knowing this fact, amoxicillin continues as the drug of choice for AOM.

Advantages to low doses

There are some advantages to prescribing the lower dose of amoxicillin. The parents or managed care plan benefits from reduced costs of treatment, there are fewer bottles of antibiotic suspension to carry home, there may be less of a mess at medicine time and possibly fewer dirty diapers to change. I wonder how many of you are silent nonconformists regarding the dose of amoxicillin for treatment of pediatric AOM?

Do you double the dose?
Write us at mrosenthal@slackinc.com and let us know your experience.