What evidence supports the recommendation for high-dose amoxicillin in children with acute otitis media?

Introduction
Occurring in more than 80% of children by the age of 3 years, the incidence and prevalence of acute otitis media (AOM) peaks in children within the first 1 to 2 years of life. Otitis media is the most common cause of doctor visits and antibiotic use in children and can become chronic and recurrent if not treated appropriately.¹ Ear pain is a common symptom amongst patients with AOM, and signs and symptoms of pain may include ear pulling, irritability, change in sleeping habits, or fever.² Acute otitis media exists on a disease continuum with otitis media with effusion (OME), which can precede or predispose the development of AOM; in OME, antibiotics are not prescribed.^1,2 In AOM, viral upper respiratory tract infection often leads to constriction and edema of the middle ear, causing disruption in mucociliary clearance and facilitating bacterial entry into the middle ear.^2,3 Though AOM is commonly considered a bacterial infection, microbiological testing of middle ear fluid has shown that in most cases (66%), the etiology of the inner ear fluid is often a mixture of bacteria and viruses.² Generally, culture specimens are not often collected for AOM in uncomplicated cases, and are typically reserved for complicated or refractory cases, which limits the identification of causative pathogens in uncomplicated disease.⁴ Prescribers rely on culture results from complicated cases of AOM and the identification of common pathogens as well as their knowledge of local susceptibility patterns to guide the prescribing of appropriate treatment for uncomplicated AOM. According to the American Academy of Pediatrics (AAP) 2013 AOM treatment guideline, the most common bacterial pathogens cultured from middle-ear fluid in children with AOM include: Streptococcus pneumoniae, non-typeable Haemophilus influenzae, and Moraxella catarrhalis, which commonly colonize the nasopharynx.² A fourth pathogen, Streptococcus pyogenes, is relatively uncommon and occurs in less than 5% of cases.

Of the bacterial pathogens, S. pneumoniae was the most frequently cultured until the introduction of the 7-valent pneumococcal vaccine (PCV7) in 2000.² Since the introduction, strains of PCV7 in vaccinated patients have largely been replaced by non-PCV strains in middle ear fluid. With the introduction of the 13-valent pneumococcal vaccine (PCV13), which covers non-PCV7 serotype 19A and has been largely implicated as a cause of multidrug-resistant S pneumoniae, bacterial pathogens continue to evolve, and isolation of S. pneumoniae and H. influenzae from cultures have become generally equal.^2,5,6  In cultures of β-lactamase positive M. cattarhalis, studies have shown spontaneous clearance in up to 75% of patients treated with amoxicillin, which is not stable against β-lactamase.^7,8

Currently, recommendations from the 2013 AAP guideline for AOM state that high-dose amoxicillin should be used as the first-line antibiotic for uncomplicated AOM.² The AAP recommends high-dose amoxicillin (eg, 80 to 90 mg/kg/day divided into 2 doses) in children who are not penicillin-allergic, do not have concurrent purulent conjunctivitis, and who have not received amoxicillin within the previous 30 days. Efficacy data from the 3 comparative antibiotic studies in children referenced by the AAP to support this recommendation are summarized in Table 1, which is primarily reliant upon efficacy in children with high-dose amoxicillin-clavulanate.^2,9,10,11  The AAP also cites amoxicillin’s relative safety, low cost, acceptable taste, and narrow spectrum of activity in comparison to other antibiotic regimens as the reasoning behind the first-line recommendation.² Additional beta-lactamase coverage (eg, amoxicillin-clavulanate at a dose of 90 mg/kg/day of amoxicillin) is recommended if the child has received amoxicillin within the past 30 days, has purulent conjunctivitis, or has a history of AOM nonresponsive to amoxicillin. In penicillin-allergic patients, cefdinir, cefuroxime, cefpodoxime, or ceftriaxone can be used, unless a history of a severe reaction to penicillin is noted. The AAP guideline acknowledges that while amoxicillin-clavulanate may be a better initial antibiotic, because of cost and adverse events, amoxicillin use according to the aforementioned criteria is appropriate in most patients for first-line treatment.

Antibiotic resistance mechanisms and recent microbiological data on causative pathogens are critical for consideration when evaluating the appropriateness of an antibiotic regimen. Penicillin resistance in S. pneumoniae is developed through genetic recombination leading to the expression of penicillin-binding proteins (PBPs) that are less susceptible to β-lactam binding.⁴ This resistance, however, can be overcome with the use of high drug concentrations achieved through maximal dosing, rendering amoxicillin active even in moderately susceptible S. pneumoniae.  High-dose amoxicillin has been shown to yield middle ear fluid levels that exceed the minimum inhibitory concentration (MIC) of S. pneumonia serotypes with intermediate penicillin resistance (MIC, 0.12 to 1 mg/mL, and many highly resistant serotypes (MIC, 2 mg/mL).² Across age groups, 87% of S. pneumoniae isolates have been shown to be susceptible to the use of high-dose amoxicillin. Since β-lactam antibiotics such as amoxicillin exhibit time-dependent killing, drug dosing in accordance with AAP recommendations every 12 hours results in a percentage of the dosing interval during which free serum concentrations (fT) exceed the MIC (fT > MIC) for 6 hours, or 50% fT > MIC.^2,4  For bacteriostasis with penicillin agents, fT > MIC of 30% is necessary, and a 50% fT > MIC is generally required for bactericidal activity.⁴ Additionally, since S. pneumoniae does not typically produce β-lactamase, use of high-dose amoxicillin prioritizes its favorable pharmacokinetic profile to use high drug concentrations to overcome penicillin resistance versus use of broad-spectrum activity against β-lactamase-producing organisms.

Literature Update
Since the 2013 AAP guideline was published, three more recent studies assessing the comparative efficacy of amoxicillin versus alternative antibiotic regimens for the treatment of AOM in children were identified in a Pubmed search conducted in November 2022.^2,12,13,14 In a retrospective cohort study of data by Frost et al on children 6 months to 12 years of age from a national claims database, antibiotic treatment failure and recurrence rates were evaluated for amoxicillin, amoxicillin-clavulanate, cefdinir, and azithromycin in uncomplicated AOM.¹² Of the 1,051,007 patients included in the analysis, more than half (56.6%) were prescribed amoxicillin (dose not specified), while 13.5% received amoxicillin-clavulanate, 20.6% cefdinir, and 9.3% azithromycin. Most treatment durations (93%) in the analysis were 10 days in length, and 61.5% were between 6 months and 5 years of age. Patients were excluded from the analysis if they had an AOM diagnosis 30 days before the start of the study period, if they had been prescribed an antibiotic within 30 days of the index period, or if they had recurrent AOM. Infection recurrence was defined as an additional antibiotic filled within 15 to 30 days after the index AOM encounter, while treatment failure was defined as any antibiotic filled within 2 to 14 days after the index AOM encounter. Overall, treatment failure and recurrence rates across the study were low, occurring in 2.2% and 3.3% of patients, respectively. Treatment failure or recurrence was found to occur more often in children prescribed amoxicillin-clavulanate (11.3%; 95% confidence interval [CI], 11.1 to 11.5), cefdinir (10%; 95% CI, 9.8 to 10.1), and azithromycin (9.8%; 95% CI, 9.6 to 10) when compared to amoxicillin (1.7%; 95% CI, 1.7 to 1.8; p<0.001 for all comparisons); this finding was observed across all age groups.

A prospective longitudinal study by Ghosh et al evaluated the use of cefpodoxime 10 mg/kg/day (n=19) versus amoxicillin-clavulanate 30 mg/kg/day (of amoxicillin; n=17) in children under 2 years of age with AOM.¹³ After 10 days of antibiotic treatment, 93.8% and 88.2% of patients achieved clinical success in the amoxicillin-clavulanate and cefpodoxime groups, respectively, with clinical success considered similar between treatment groups.

In another retrospective cohort study conducted by Chu et al, the use of high-dose amoxicillin-clavulanate (eg, 80 to 90 mg/kg/day of amoxicillin) was evaluated in 400 children with AOM.¹⁴ Nearly a quarter of patients (n=94) included in the study had complicated AOM. In the study, multivariate logistic regression was used to analyze the relationship between amoxicillin dose and AOM prognosis. Dosage was considered appropriate if within ± 10% of the AAP guideline suggested dosing (eg, 80 to 90 mg/kg/day of amoxicillin) and was considered over or under dosing if outside the ±10% range. The assessment of the treatment outcome was based on medical record information within 14 days of the antibiotic prescription expiration. Overall, the high dose regimen was associated with fewer patients with a poor AOM prognosis versus standard dose (16.7% versus 27.9%; p=0.41), however, this finding was not statistically significant. In the subgroup of patients < 2 years of age with bilateral disease, the high-dose regimen was associated with significant improvements in AOM prognosis versus standard dosing (odds ratio, 1.63; 95% CI, 1.02 to 2.59).

Conclusion
Since the 2013 recommendations for amoxicillin as first-line treatment in children with AOM in children were published, the distribution of causative organisms, as well as multidrug resistance, has continued to evolve. Since the guideline, the continued efficacy of high-dose amoxicillin in comparison to other agents has been evaluated in 2 large retrospective cohort studies, and in 1 prospective study.^2,12,13,14 Though the findings by Ghosh et al found similar success rates between amoxicillin-clavulanate and cefpodoxime for AOM, this finding is limited by the lower-than-guideline-recommended dosing of amoxicillin (eg, 30 mg/kg/day) used in the study, as well as the extremely small sample size of patients that were evaluated.¹³ Additionally, the findings from Chu et al are limited by a quarter of the patient population having complicated AOM, which often requires a different antibiotic regimen.¹⁴ In the study by Chu et al, patients under 2 years of age with bilateral disease saw improvements in outcomes with high-dose amoxicillin. Overall, based on lower treatment failure and recurrence rates of AOM with the use of amoxicillin in the large prospective cohort study by Frost et al and the illustrated benefits of high-dose treatment in specific groups in Chu et al, these studies support the continued efficacy of amoxicillin for the treatment of uncomplicated AOM despite microbiologic changes over the past decade. Based on these studies, the AAP recommendations for amoxicillin and amoxicillin-clavulanate as first-line and second-line treatment options remain applicable for pediatric AOM. Future shifts in otopathology, however, will likely call into question the continual use of amoxicillin as a first-line agent.^12,14

References

1. Kerschner Joseph E, Preciado Diego. Otitis media. In: Kliegman RM, St Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson’s Textbook of Pediatrics. 21st ed. Elsevier; 2020: chap 658. Accessed November 1, 2022. https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780323529501007513
2. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013;131(3):e964-e999. doi:10.1542/peds.2012-3488
3. Pettigrew MM, Gent JF, Pyles RB, Miller AL, Nokso-Koivisto J, Chonmaitree T. Viral-bacterial interactions and risk of acute otitis media complicating upper respiratory tract infection. J Clin Microbiol. 2011;49(11):3750-3755. doi:10.1128/JCM.01186-11
4. Molloy L, Barron S, Khan N, Abrass E, Ang J, Abdel-Haq N. Oral β-lactam antibiotics for pediatric otitis media, rhinosinusitis, and pneumonia. J Pediatr Health Care. 2020;34(3):291-300. doi:10.1016/j.pedhc.2019.11.001
5. Pichichero ME, Casey JR. Emergence of a multiresistant serotype 19A pneumococcal strain not included in the 7-valent conjugate vaccine as an otopathogen in children. JAMA. 2007;298(15):1772-1778. doi:10.1001/jama.298.15.1772
6. Kawai K, Adil EA, Barrett D, Manganella J, Kenna MA. Ambulatory visits for otitis media before and after the introduction of pneumococcal conjugate vaccination. J Pediatr. 2018;201:122-127.e1. doi:10.1016/j.jpeds.2018.05.047
7. Klein JO. Microbiologic antibacterial drugs for acute otitis media. Pediatr Infect Dis J. 1993;12(12): 973–975.
8. Barnett ED, Klein JO. The problem of resistant bacteria for the management of acute otitis media. Pediatr Clin North Am. 1995;42(3):509–517.
9. 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(5):405-413. doi:10.1097/01.inf.0000065688.21336.fa
10. 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(9):829-837. doi:10.1097/00006454-200109000-00002
11. 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(2):95-104. doi:10.1097/00006454-200002000-00002
12. Frost HM, Bizune D, Gerber JS, Hersh AL, Hicks LA, Tsay SV. Amoxicillin versus other antibiotic agents for the treatment of acute otitis media in children. J Pediatr. 2022;S0022-3476(22)00674-6. doi:10.1016/j.jpeds.2022.07.053
13. Ghosh A, Chatterjee S. Comparison of efficacy and safety of cefpodoxime and amoxicillin-clavulanate potassium in paediatric acute otitis media in children below two years: a prospective longitudinal study. J Clin Diagn Res. 2017;11(6):FC01-FC04. doi:10.7860/JCDR/2017/25252.9955
14. Chu CH, Wang MC, Lin LY, et al. High-dose amoxicillin with clavulanate for the treatment of acute otitis media in children. Scientific World Journal. 2014;2013:965096. Published 2014 Jan 6. doi:10.1155/2014/965096

Prepared by:
Sabine Puglia, PharmD Candidate Class of 2023
University of Illinois at Chicago College of Pharmacy

Reviewed by:
Christie Denton, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

December 2022

The information presented is current as of November 23, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.