Shortened Antimicrobial Treatment for Acute Otitis Media in Young Children

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Hoberman A, et al. "Shortened Antimicrobial Treatment for Acute Otitis Media in Young Children". New England Journal of Medicine. 2016. 375(25):2446-2456.
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Clinical Question

In pediatric patients aged 6-23 months with acute otitis media requiring antibiotics, is a 5 day course of amoxicillin-clavulanate as effective at resolving symptoms as a 10 day course?

Bottom Line

A reduced duration antimicrobial treatment is not recommended for young children with acute otitis media. Shorter durations results in less favorable therapeutic outcomes and showed no reduction in the amount of adverse events or antimicrobial resistance.

Major Points

The study evaluated reduced-duration 5-day course with standard-duration 10-day course in children with acute otitis media (AOM). AOM is a common acute illness in children aged 6-23 months. A reduced course of antibiotic would be easier for patient adherence and adult administration and possible decrease adverse events associated with antimicrobial therapy. As a secondary outcome the study aimed to see if antibiotic resistance would be prevented by a shorter course of therapy.

Five hundred twenty children aged 6 to 23 months were randomized to a 10 or 5 day course of amoxicillin-clavulanate. Children were assessed during treatment by a telephone conversation with the parent and at an end-of-treatment office visit. Parents were also asked to use the Acute Otitis Media–Severity of Symptoms (AOM-SOS) scale to evaluate the child’s symptoms daily. The child was also evaluated in office every 6 weeks for the duration of the respiratory-infection season (October 1 through May 31). The primary outcome was the percentage of children who had clinical failure after treatment of the index infection. Secondary outcomes included recurrence of AOM, total days of antimicrobial treatment during the respiratory-infection season, and effusion rate.

A reduction in clinical failure was seen in the 10 day treatment group compared to the 5 day treatment group (39 of 238 [16%] vs 77 of 229 children [34%]; 95% CI, 9 to 25; NNT to prevent clinical failure = 6). Secondary outcome rates of antimicrobial resistance and adverse events were not shown to be lower in the 5-day treatment duration versus the 10 day. This study therefore, makes a strong case for use of a 10 day treatment duration of amoxicillin-clavulanate for patients aged 6-23 months, to prevent clinical failure. Limitations of this study include the age of children was restricted to those 6-23 months of age and therefore no conclusions can be generalized to older children, and only one antibiotic was evaluated for effectiveness.

Guidelines

Diagnosis and Management of Acute Otitis Media in Children (American Academy of Pediatrics)

  • Amoxicillin is the first line of therapy for children with AOM. (Randomized control trial)
  • If the infection is severe, or involves Haemophilus influenzae or Moraxella catarrhalis, it is recommended to use high dose amoxicillin-clavulanate (90 mg/kg/day of amoxicillin, with 6.4 mg/kg/day of clavulanate in 2 divided doses) for added coverage and efficacy. (Randomized control trials)
  • The optimal duration of therapy for patients with AOM is uncertain. Studies comparing standard duration of treatment (10 days) to short-duration treatment (1–7 days) were often characterized by limitations and varying results.
  • The results favoring standard 10-day therapy have been most significant in children younger than 2 years and suggestive of increased efficacy in those 2 to 5 years of age. Thus, for younger children and for children with severe disease, a standard 10-day course is recommended. (Microbiologic studies and expert opinion)
  • For children 6 years of age and older with mild to moderate disease, a 5- to 7-day course is appropriate. (Microbiologic studies and expert opinion)

These guidelines support the evidence found in the study that a 10 day course of antibiotic therapy is better at relieving symptoms of AOM than a 5 day course of therapy in young children.

Design

  • Randomized, double-blind, placebo-controlled trial
  • N=515
    • 5 days of amoxicillin-clavulanate followed by 5 days of placebo (n=258)
    • 10 days of amoxicillin-clavulanate (n=257)
  • Setting: Children’s Hospital of Pittsburgh, affiliated pediatric practices, and Kentucky Pediatric and Adult Research in Bardstown, Kentucky
  • Enrollment: January 2012 to September 2015
  • Mean follow-up:
    • Assessed on day 4, 5, or 6 by telephone conversations with parents
    • Assessed on day 12, 13, or 14 at an end-of treatment office visit
    • In-office assessments were also done every 6 weeks through the end of respiratory-infection season (October 1st to May 31st)
    • An end-of-study assessment was made through an office visit during the following September
    • Those children who had to receive rescue treatment due to clinical failure had an additional post-treatment assessment
  • Analysis: Intention-to-treat, non-inferiority
  • Primary outcome: Clinical effectiveness

Population

Inclusion Criteria

  • Child has received at least 2 doses of pneumococcal conjugate vaccine
  • Diagnosed with AOM on the basis of three criteria
    • Onset of symptoms within the preceding 48 hours that parents rated with a total score of 3 or more on the AOM-SOS scale. The scale consists of seven discrete items — tugging of ears, crying, irritability, difficulty sleeping, diminished activity, diminished appetite, and fever. Parents are asked to rate these symptoms, compared with the child’s usual state, as “none,” “a little,” or “a lot,” with corresponding scores of 0, 1, and 2. Total scores range from 0 to 14, with higher scores indicating greater severity of symptoms.
  • The presence of middle-ear effusion  
  • Moderate or marked bulging of the tympanic membrane or slight bulging accompanied by apparent otalgia or marked tympanic-membrane erythema.

Exclusion Criteria

  • Children who were allergic to Amoxicillin.
  • Children who had tympanic-membrane perforation or another illness.
  • Children who had received more than one dose of an antimicrobial agent within the previous 96 hours.

Baseline Characteristics.

  • Demographics: Child 6 to 23 months old, 54% male.
  • 58% of children had exposure to other children.
  • Number of ears affected, 51% one year.
  • AOM-SOS score 37% scored between an 8 and 11 (as defined in inclusion criteria).

Interventions

  • The intervention was considered a 5-day course of amoxicillin-clavulanate in one bottle followed by a 5-day course of placebo in a second bottle.
    • The placebo was made to be similar to the amoxicillin-clavulanate in color, odor, taste, and texture.
  • The control was considered a 10-day course of amoxicillin-clavulanate at a total daily dose of 90 mg/6.4 mg in two different bottles.
  • Administration of appropriate doses of acetaminophen to children who had a fever or pain was suggested.
  • Children were considered to have clinical failure if they had worsening symptoms, or if they did not have complete resolution of symptoms. These children were given rescue treatment.
    • Rescue treatment consisted of amoxicillin-clavulanate, or alternatively, ceftriaxone or cefdinir.
  • For a first recurrence of AOM (episode occurring after day 16 of the index episode) children were treated a second time with their assigned regimen and were followed.
  • For a second recurrence of AOM (or any further recurrences) rescue treatment was given, and a specimen was taken for culturing.

Outcomes

Comparisons are 5-day vs 10-day treatment. Clinical failure is defined when children had worsening of symptoms or of otoscopic signs of infection (primarily tympanic-membrane bulging) or if they did not have complete or nearly complete resolution of symptoms and signs attributable AOM at the end of treatment.

Primary Outcomes

Children who had clinical failure after treatment of index infection (5-day vs. 10-day)
77 of 229 children [34%] vs 39 of 238 [16%]; 95% CI, 9 to 25; NNT prevent clinical failure 6

Secondary Outcomes

Rate of recurrence of AOM Composite effusion, unilateral effusion, bilateral effusion
Residual effusion 62% vs 65% (P = 0.35)
Recurrences among children with residual effusion vs. no residual effusion
48% vs 29% (P < 0.001)

Subgroup Analysis

The results in subgroups consistently favored the group of children assigned to receive the 10-day treatment.

Adverse Events

There were no differences between the study groups. Diarrhea

  • 29% vs 30%

Dermatitis of the Diaper Area that Required a Prescription Antifungal

  • 34% vs 33%

Criticisms

  • The results of the study cannot be generalized to children over the age of 2.
  • Of the 1569 children eligible, only 520 were enrolled in the study, limiting the external validity of the outcomes.
  • Results are only based on one antibiotic, which does not allow the outcomes to be generalized to other antibiotic regimens. (1)

Funding

Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Research Re-sources; ClinicalTrials.gov number, NCT01511107.

Further Reading

  1. http://www.jwatch.org/na43069/2016/12/21/treatment-otitis-media-how-long-long-enough
  2. http://pediatrics.aappublications.org/content/113/5/1451

Authors

Taylor Hodle Alexandra Grudeski Emily Kneeream Griffin DiBileo Arielle Domashinski Brittany Gurreri