By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
SYNOPSIS: Review of a large database reveals that, for children treated for acute sinusitis, amoxicillin and amoxicillin-clavulanate yield similar rates of treatment failure. However, medication side effects are more common when amoxicillin-clavulanate is used.
SOURCE: Savage TJ, Kronman MP, Sreedhara SK, et al. Treatment failure and adverse events after amoxicillin-clavulanate vs amoxicillin for pediatric acute sinusitis. JAMA 2023;330:1064-1073.
Acute sinusitis in children accounts for approximately 5 million antibiotic prescriptions each year in the United States. A majority of two of the main causative organisms, Haemophilus influenzae and Moraxella catarrhalis, produce beta-lactamases, while the other main causative organism, Streptococcus pneumoniae, does not produce beta-lactamases. The 2012 Infectious Diseases Society of America guidelines suggested amoxicillin-clavulanate as the first-line treatment, while the 2013 American Academy of Pediatrics guidelines recommended either amoxicillin or amoxicillin-clavulanate. A report this year noted that approximately two-thirds of children treated for acute sinusitis in the United States receive one of these two agents.
Widespread use of pneumococcal vaccines during the past two decades could have altered the microbiological epidemiology of acute sinusitis in children, and it is not clear which recommended agent, amoxicillin or amoxicillin-clavulanate, is a better initial treatment choice. Thus, Savage and colleagues from Boston and Seattle studied treatment failures and adverse effects of treatment of children with acute sinusitis who received either amoxicillin or amoxicillin-clavulanate.
Using the MarketScan Commercial Claims and Encounters Database of commercially insured patients, the investigators reviewed data from children younger than 18 years of age treated for acute sinusitis from the beginning of 2017 through the end of 2021. Children who received recent sinusitis treatment (or an antibiotic for any other reason) during the 30 days prior to enrollment and children who received concurrent prescriptions for multiple antibiotics were excluded from analysis. “Treatment failure” during the two weeks after the initial prescription was defined as receiving a different antibiotic prescription, having an emergency department visit or an inpatient hospitalization for sinusitis, or having inpatient care for a complication of sinusitis.
A total of 371,550 patients were initially included in the study cohort; after applying exclusion criteria, 320,141 were included in the final cohort. After propensity score matching, 99,471 children were included in each of the two study groups. Subjects were included from all 50 U.S. states.
Treatment failures were identified in 1.8% of patients, which was statistically similar between the two groups. Most treatment failures manifested by the addition of a different antibiotic during the initial treatment course. Emergency or inpatient care for sinusitis was rare, occurring in far less than 0.1% of study subjects, but was statistically more likely when amoxicillin was used initially. Adverse events, specifically gastrointestinal symptoms requiring medical care (1% of patients) or yeast infection (0.4% of patients), were more common with amoxicillin-clavulanate than with amoxicillin. Anaphylaxis (0.4%) was seen similarly between treatment groups.
The authors nicely detailed strengths and limitations of their large study and reasonably concluded that treatment failure was rare in children treated with either amoxicillin or amoxicillin-clavulanate for acute sinusitis and that the choice of antibiotic did not affect treatment failure. They noted more gastrointestinal adverse symptoms and more yeast infections among children treated with amoxicillin-clavulanate and think that these new data can inform future clinical treatment decisions.
COMMENTARY
This helpful new study reassures us that even in an era of widespread pneumococcal vaccination, acute sinusitis in children responds similarly well to amoxicillin as to amoxicillin-clavulanate (at least as far as the treatment failures identified in this study are concerned). Realizing that adverse effects of treatment are more common with amoxicillin-clavulanate than with amoxicillin, clinicians might choose to favor amoxicillin as first-line treatment of sinusitis in children.
While this is study is good and helpful, several questions remain unanswered.
First, was either antibiotic even necessary?
The diagnosis of sinusitis is challenging in children — partly because the symptoms and the signs and even the imaging findings of viral upper respiratory infections overlap with those of bacterial sinusitis. Furthermore, with pneumococcal vaccination leaving Haemophilus and Moraxella as the primary microbiologic causes of pediatric ear and sinus infections and with beta-lactamase production seen in the majority of these two pathogens, one would have expected more treatment failures with amoxicillin than with amoxicillin-clavulanate; the lack of worse outcomes between these two treatment groups raises the question of how necessary any antibiotic actually was for some of the children included in this study.1
Expert advice on diagnosing sinusitis in children is accepted today as it was 10 years ago, even if this advice is not uniformly applied. Specifically, bacterial sinusitis should be diagnosed and treated in children when: nasal discharge or cough persists without improvement for more than 10 days after the onset of what seems to be a viral upper respiratory infection, there is worsening cough or nasal discharge or fever, or there is high fever with purulent nasal discharge for at least three days.2-4 However, more recent data show that seeming new or worsening bouts of sinusitis actually can be due to the beginning of a subsequent viral infection rather than to bacterial disease.5 It is possible that many children in the Savage study had viral infections affecting their sinus(es) rather than actual bacterial sinusitis.
In a recent randomized trial, treatment with amoxicillin-clavulanate was compared with placebo treatment for 515 children with acute sinusitis.6 Antibiotic treatment was associated with shorter (seven vs. nine days) durations of symptoms.6 In this study, nasal swab samples were tested with bacterial culture; children without identified S. pneumoniae, H. influenzae, and M. catarrhalis did not improve differently with antibiotic treatment than with placebo.6 The color of nasal secretions was not related to the response to treatment.6 These data suggest that organisms found in nasal secretions might predict the need for antibiotics, and they remind us that the visible character of the secretions is not related to the bacterial vs. viral etiology of the illness.
Second, assuming that antibiotic therapy did help some of the children in this study, did amoxicillin-clavulanate lead to more rapid resolution of symptoms?
The database used by Savage and colleagues followed only severe undesirable outcomes that prompted additional medical care. They did not record how quickly symptoms resolved. Thus, it is not clear that the two treatments, amoxicillin and amoxicillin-clavulanate, actually were similarly effective in prompting clinical resolution of symptoms.
Third, how common were symptomatically bothersome medication side effects that did not prompt further medical care?
Again, this study was not designed to determine the frequency of bothersome but less dangerous medication effects. Other studies suggest that side effects of antimicrobial use in children are much more frequent than the 1% rate identified by Savage and colleagues.
Fourth, might dosing have been as important as antimicrobial selection?
The database used in this study did not record doses of the prescribed antibiotics. Higher doses of the amoxicillin component of treatment (80 mg/kg/day to 90 mg/kg/day instead of 45 mg/kg/day) might be necessary if pneumococcus (with known tolerance to lower doses) still is a major etiologic contributor to sinusitis in children. It is conceivable that different dosing of the amoxicillin component in Savage’s study might have accounted for some of the treatment failures. However, pneumococcus seems to be decreasingly frequent as a cause of sinusitis, and the beta-lactamase producers are relatively more common causes of sinusitis in children, leading at least some experts to revise decade-old recommendations and now support low-dose (45 mg/kg/day) amoxicillin with clavulanate as first-line treatment of children with sinusitis.1
Further studies could help answer these questions. Only then will we really know if amoxicillin and amoxicillin-clavulanate lead to differing rapidity of symptomatic improvement and/or differing risks of bothersome adverse reactions. In the meantime, in view of major treatment failures, amoxicillin and amoxicillin-clavulanate seem similarly effective in treating acute sinusitis in children.
REFERENCES
- Wald ER, DeMuri GP. Antibiotic recommendations for acute otitis media and acute bacterial sinusitis: Conundrum no more. Pediatr Infect Dis 2018;37:1255-1257.
- DeMuri G, Wald ER. Acute bacterial sinusitis in children. Pediatr Rev 2013;34:429-37; quiz 437.
- Wald ER, Applegate KE, Bordley C, et al. Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years. Pediatrics 2013;132:e262-80.
- Leung AK, Hon KL, Chu WC. Acute bacterial sinusitis in children: An updated review. Drugs Context 2020;9:2020-9-3.
- DeMuri GP, Eickhoff JC, Gern JC, Wald ER. Clinical and virological characteristics of acute sinusitis in children. Clin Infect Dis 2019;69:1764-1770.
- Shaikh N, Hoberman A, Shope TR, et al. Identifying children likely to benefit from antibiotics for acute sinusitis: A randomized clinical trial. JAMA 2023;330:349-358.
