Side effects of antibiotics for frequent ear infections in children

Long-term and repeated use of antibiotics in children with recurrent otitis media is associated with a number of clinically significant side effects, which can be divided into immediate (acute), microbiological and long-term effects.

I. Immediate (acute) side effects

A meta-analysis of 82 studies showed that diarrhea is the most common side effect of antibiotic therapy for AOM: it develops in one in five children receiving high-dose amoxicillin-clavulanate (NNH=9) and in one in eight taking amoxicillin (NNH=15). A Cochrane review of antibiotics for OME confirmed a higher risk of diarrhea, vomiting and skin rash. According to the AAP (2021), antibiotic-associated adverse events account for almost 50% of all emergency department visits for side effects of systemic medicines in children. ^[1][2][3]

II. Antibiotic resistance

This is the most serious consequence of long-term antibiotic use. The AAP guideline (2013) states directly that the modest benefit of antibiotic prophylaxis (preventing ~1.5 episodes of AOM a year, NNT=5) must be weighed against its contribution to bacterial resistance. ^[4]

Specific data on resistance in AOM:

• The meta-analysis by Mather et al. (2019, 48 studies, 15,871 samples) showed that about 15% of bacterial isolates in AOM are resistant to amoxicillin. Amoxicillin-clavulanate remains effective against 95% of isolates ^[5]
• The RCT by Hoberman et al. (NEJM, 2016) showed that after a course of antibiotics the proportion of penicillin-nonsusceptible S. pneumoniae strains in the nasopharynx increases, although colonization returns to baseline over time ^[6]
• Children with recurrent and persistent AOM have a predominance of antibiotic-resistant S. pneumoniae and β-lactamase-producing H. influenzae, which makes later treatment more difficult ^[7]

III. Disruption of the gut microbiome (dysbiosis)

The systematic review by McDonnell et al. (2021, 12 studies) found that antibiotics in children cause: ^[8]

• A significant decrease in α-diversity of the microbiome (meta-analysis of RCTs: Shannon index −0.86; 95% CI −1.59 to −0.13 for macrolides)
• A decrease in Bifidobacteria (5 studies) and Lactobacillus (2 studies), key commensals
• An increase in Proteobacteria (E. coli and others), potentially pathogenic microorganisms

The Finnish cohort study by Korpela et al. (2016, n=142 children) showed that macrolides leave a much longer-lasting mark on the microbiome than penicillins: fewer Actinobacteria, more Bacteroidetes and Proteobacteria, lower bile salt hydrolase activity and more macrolide resistance genes. ^[9]

IV. Clostridioides difficile infection (CDI)

The prospective study by Mitchell et al. (1996) showed that after a 10-day course of amoxicillin-clavulanate for otitis, toxigenic C. difficile was found in 13% of children (27% among those who developed diarrhea vs 7% without diarrhea, p=0.03). ^[10]

According to a large surveillance study, 71% of CDI cases in children are community-acquired, and most develop after outpatient antibiotics for otitis, sinusitis or respiratory infections. The highest CDI risk is associated with clindamycin (OR 73.0), third-generation cephalosporins (OR 16.3) and amoxicillin-clavulanate, while amoxicillin carries the lowest risk among commonly prescribed antibiotics. ^{[3][11][12][13]}

V. Long-term consequences: allergic and metabolic diseases

The largest cohort study, by Beier et al. (2025, n=1,091,449 children) with sibling controls, found dose-dependent associations between antibiotics in the first 2 years of life and: ^[14]

The cohort study by Aversa et al. (2021, n=14,572, Mayo Clinic) confirmed associations with asthma, allergic rhinitis, atopic dermatitis, celiac disease, obesity and ADHD (HR 1.20–2.89). The study by Donovan et al. (2020, n=152,622) showed 20% higher odds of asthma for each additional course of antibiotics in infancy, with a stronger effect for broad-spectrum antibiotics. ^[15][16]

An important caveat: these associations may be partly explained by confounding by indication (children who receive more antibiotics are more prone to infections and atopy to begin with). The sibling control in the Beier et al. study minimizes but does not fully eliminate this bias. ^[14]

VI. Effect on the nasal microbiome and asthma risk

The cohort study by Toivonen et al. (2021, n=697) showed that 2 or more courses of antibiotics in the first year of life are associated with a 4% absolute increase in the risk of asthma by age 7 (p=0.006). This effect is partly mediated by changes in the nasal microbiome — in particular, early depletion of Moraxella, which accounts for 16% of the total effect of antibiotics on the development of asthma. ^[17]

VII. Practical conclusions

The AAP guideline on antibiotic therapy for AOM (2013) and the AAP antibiotic stewardship policy (2021) recommend: ^[3][4]

• Antibiotic prophylaxis for recurrent AOM is not recommended — the modest benefit (NNT=5 per year) does not justify the risks of resistance and dysbiosis
• For non-severe AOM — consider watchful waiting, which avoids antibiotics in ~65% of children
• Prefer amoxicillin (narrow spectrum, lowest risk of CDI and dysbiosis) over amoxicillin-clavulanate and cephalosporins
• Avoid macrolides (azithromycin) — they have the most pronounced and long-lasting effect on the microbiome ^[9]
• For recurrent AOM, consider tympanostomy as an alternative to repeated courses of antibiotics ^[18]