By Richard R. Watkins, MD, MS, FACP, FIDSA
Associate Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General Medical Center, Akron, OH
Dr. Watkins reports that he has received research support from Allergan.
SYNOPSIS: A randomized, placebo-controlled clinical trial determined that in children 6-23 months of age with acute otitis media, five days of amoxicillin-clavulanate resulted in more clinical failure compared to a 10-day course of therapy.
SOURCE: Hoberman A, Paradise JL, Rockette HE, et al. Shortened antimicrobial treatment for acute otitis media in young children. N Engl J Med 2016;375:2446-2456.
Results from clinical trials have shown antibiotics to be beneficial in treating acute otitis media (AOM) in children. However, controversy exists about the optimal duration of therapy because of methodological flaws in previous studies. Therefore, Hoberman et al sought to clarify whether outcomes would be similar between a standard 10-day course of antibiotics and five days of treatment.
The study enrolled children aged 6-23 months diagnosed with AOM based on three criteria: onset of symptoms in the preceding 48 hours, the presence of a middle-ear suffusion, and moderate or marked bulging of the tympanic membrane or slight bulging accompanied by otalgia or marked tympanic membrane erythema. All had received at least two doses of pneumococcal conjugate vaccine. At each research site, children were randomized to receive either a 10-day course of amoxicillin-clavulanate or a five-day course followed by five days of placebo. Children were followed for clinical failure, which was defined as worsening symptoms or worsening otologic signs of infection, or if they did not have complete resolution of signs and symptoms by the end of treatment. The primary outcome measured was the percentage of children who had clinical failure after treatment of the index infection. Secondary outcomes included symptom burden from day 6 to day 14, rates of recurrence of AOM, total days of antibiotics during the respiratory-infection season, rates of nasopharyngeal colonization, use of other healthcare services, rates of missed work by parents, and parental satisfaction with the treatment.
Of 1,569 children who were screened, 257 were randomized to the 10-day group and 258 to the five-day group. Clinical failure was higher in children treated for five days compared to 10 days (77 of 229 [34%] vs. 39 of 238 [16%], 95% confidence interval [CI], 9-25). Subgroup analysis consistently favored the 10-day group. When the two groups were combined, clinical failure rates were higher among children with exposure to ≥ three children for ≥ 10 hours per week vs. those with less exposure (P = 0.02) and in those with bilateral AOM vs. unilateral (P < 0.001). Also, the clinical failure rate was higher when there were more characteristics considered to be unfavorable based on clinical experience and/or previously published findings. The mean symptom scores from day 6 to day 14 were 1.61 in the five-day group and 1.34 in the 10-day group (P = 0.07), and at the day 12-14 assessment were 1.89 vs. 1.20, respectively (P = 0.001). Furthermore, the percentage of children whose symptom scores decreased > 50% from baseline was worse in the five-day group (181 of 227 children [80%] vs. 211 of 233 [91%], P = 0.003). Among children with recurrent AOM, the clinical failure rate was consistently higher in the five-day group (28%) than in the 10-day group (19%), and the criterion for non-inferiority of the five-day treatment course was not met. After the course of treatment, the level of nasopharyngeal colonization with penicillin-susceptible Streptococcus pneumoniae decreased in both groups. The mean number of days on which children received antibiotics during the respiratory-infection season was 21 in the 10-day group and 15 in the five-day group (P < 0.001), mainly due to the index infection. Adverse events were similar between both groups (primarily diarrhea and diaper rash) and there were no significant differences in the rates of use of other healthcare services, missed work by parents, or levels of parental satisfaction with the treatment.
AOM is the most common condition for which children are prescribed antibiotics, often for a five- to 10-day course. Shorter courses of antibiotics theoretically should lead to less disruption in the gut microbiome, fewer adverse events, less potential to spread antimicrobial resistance, and reduced costs. Indeed, the prevailing mantra about antibiotics is that “shorter is better” and that physicians should allow patients to stop antibiotics as early as possible after resolution of symptoms of infection.1 However, concerns about the downsides of antibiotics must be balanced against the potential of undertreating an acute infection and the risk of a recurrence. The study by Hoberman et al challenges the notion that a shorter course of antibiotics is always beneficial compared to the standard duration, at least for AOM. It reminds us about being careful to avoid a “one-size-fits-all” approach when deciding about how long to prescribe antibiotics for our patients.
Despite the clear results that showed 10 days of amoxicillin-clavulanate led to less clinical failure than five days without an increase in adverse events, the study had some limitations worth mentioning. First, it was not designed to assess outcomes in older children or those with risk factors for AOM, such as a cleft palate. Second, as an accompanying editorialist noted, studies on AOM are inherently difficult due to viral coinfections, antibiotic resistance, varying age of subjects, and a high rate of spontaneous resolution.2 How these factors affected the results of the present study is uncertain. Nonetheless, in children younger than 2 years of age with AOM, 10 days of amoxicillin-clavulanate should remain the standard of care. Researchers should be encouraged to conduct further pragmatic studies on the duration of antibiotics for other infections.
- Spellberg B. The new antibiotic mantra — “shorter is better.” JAMA Intern Med 2016;176:1254-1255.
- Kenna MA. Acute otitis media — The long and the short of it. N Engl J Med 2016;375:2492-2493.