The current expectation is that serotype 19A, the most frequently multidrug-resistant serotype that emerged after PCV7 was introduced in 2000, will decline by the end of 2013. Other classic pneumococcal otopathogen serotypes expressing resistance to amoxicillin have declined since 2004, as has the overall prevalence of AOM due to pneumococcus. Since 2004, more than 50% of recently antibiotic-treated or recurrent AOM appear to be due to nontypeable Haemophilus influenzae (ntHi), and more than half of these produce beta-lactamase. (Pediatr. Infect. Dis. J. 2004;23:829-33; Pediatr. Infect Dis. J. 2010;29:304-9). So more than 25% of recently antibiotic-treated AOM patients would be expected to have amoxicillin-resistant pathogens by virtue of beta-lactamase.
Is this a reasonable rationale for the first-line therapy for both AOM and ABRS to be standard (some would call low) dose, but beta-lactamase stable, amoxicillin-clavulanate at 45 mg/kg per day divided twice daily? This is the argument utilized in the 2012 IDSA ABRS guidelines. However, based on the same data, the AAP 2013 AOM guidelines conclude that high-dose amoxicillin without clavulanate should be used for first-line empiric therapy of AOM.
A powerful argument for the AAP AOM guidelines is the expectation that half of all ntHi, including those that produce beta-lactamase, will spontaneously clear without antibiotics. This is more frequent than for pneumococcus, which has only a 20% spontaneous remission. Data from our laboratory in Kansas City showed that up to 50% of the ntHi in persistent or recurrent AOM produce beta-lactamase; however, less than 15% do so in AOM when not recently treated with antibiotics (Harrison, C.J. The Changing Microbiology of Acute Otitis Media, in "Acute Otitis Media: Translating Science into Clinical Practice," International Congress and Symposium Series. 265:22-35. Royal Society of Medicine Press, London, 2007). How powerful then is the argument to add clavulanate and to use low-dose amoxicillin?
ntHi considered
First consider the contribution to amoxicillin failures by ntHi. Choosing a worst-case scenario of all ABRS having the microbiology of recently treated AOM, we will assume that 60% of persistent/recurrent AOM (and by extrapolation ABRS) is due to ntHi, and 50% of these produce beta-lactamase. Now factor in that 50% of all ntHi clear without antibiotics. The overall expected clinical failure rate for amoxicillin due to beta-lactamase producing ntHi in recurrent/persistent AOM (and by extrapolation ABRS) is 15% (0.6 × 0.5 × 0.5 = 0.15).
In contrast, let us assume that recently untreated ABRS has the same microbiology as recently untreated AOM. Then 45% would be due to ntHi, and 15% of those produce beta-lactamase. Again 50% of all the ntHi spontaneously clear without antibiotics. The expected clinical failure rate for amoxicillin would be 3%-4% due to beta-lactamase–producing ntHi (0.45 × 0.15 × 0.50 = 0.034). This relatively low rate of expected amoxicillin failure for a noninvasive AOM or ABRS pathogen does not seem to mandate addition of clavulanate.
Further, the higher resistance based on beta-lactamase production in ntHi that was quoted in the ABRS 2012 IDSA guidelines were from isolates of children who had tympanocentesis mostly for persistent or recurrent AOM. So, my deduction is that it is logical to use the beta-lactamase–stable drug combination as second-line therapy, that is, in persistent or recurrent AOM and by extrapolation, also in persistent or recurrent ABRS, but not as first-line therapy.
I also am concerned about using a lower dose of amoxicillin because this regimen would be expected to cover less than half of pneumococci with intermediate resistance to penicillin and none with high levels of penicillin resistance. Because pneumococcus is the potentially invasive and yet still common oto- and sinus pathogen, it seems logical to optimize coverage for pneumococcus rather than ntHi in as many young children as possible, particularly those not yet fully PCV13 immunized. This means high-dose amoxicillin, not standard-dose amoxicillin.
This high-dose amoxicillin is what is recommended in the 2013 AAP AOM guidelines. So I feel comfortable, based on the available AOM data, using high-dose amoxicillin (90 mg/kg per day divided in two daily doses) as empiric first-line therapy for non–penicillin-allergic ABRS patients. I would, however, use high-dose amoxicillin-clavulanate as second-line therapy for recurrent or persistent ABRS.
Summary
Most of us wish to follow rules and recommendations from groups of experts who laboriously review the literature and work many hours crafting them. However, sometimes we must remember that such rules are, as was stated in "Pirates of the Caribbean" in regard to "parlay," still only guidelines. When guidelines conflict and practicing clinicians are caught in the middle, we must consider the data and reasons underpinning the conflicting recommendations. Given the AAP AOM 2013 guidelines and examination of the available data, I am comfortable and feel that I am doing my part for antibiotic stewardship by using the same first- and second-line drugs for ABRS as recommended for AOM in the 2013 AOM guidelines.