Twice-Daily (BD) Dosing of Amoxyclav is Superior to Three-Times-Daily (TDS) Dosing in Infants
For infants, amoxicillin-clavulanate (Amoxyclav) should be dosed twice daily (BD) rather than three times daily (TDS), as this regimen provides equivalent clinical efficacy with significantly less diarrhea and better adherence. 1
Evidence-Based Dosing Recommendations
Standard Dosing for Infants
For infants under 12 weeks (<3 months): The FDA-approved dose is 30 mg/kg/day of the amoxicillin component divided every 12 hours (BD), using the 125 mg/5 mL oral suspension 1
For infants 12 weeks (3 months) and older: The recommended dose is 45 mg/kg/day divided every 12 hours (BD) for otitis media, sinusitis, lower respiratory tract infections, and more severe infections 1
For less severe infections in infants ≥3 months: 25 mg/kg/day divided every 12 hours (BD) is appropriate 1
High-Dose Regimen When Indicated
- For severe infections or resistant organisms: The Infectious Diseases Society of America recommends 90 mg/kg/day of the amoxicillin component in 2 divided doses (BD) for infants with risk factors including age <2 years, daycare attendance, recent antibiotic use, or incomplete Haemophilus influenzae type b vaccination 2, 3, 4
Why BD is Superior to TDS
Clinical Trial Evidence
A pivotal FDA trial in 575 pediatric patients (aged 2 months to 12 years) demonstrated that the every 12 hours regimen had significantly lower diarrhea rates compared to every 8 hours dosing: 14% versus 34% (p<0.05) 1
Severe diarrhea or withdrawal due to diarrhea occurred in only 3% of BD patients versus 8% of TDS patients 1
Clinical cure rates were equivalent between regimens: 87% for BD versus 82% for TDS at end of therapy 1
A 2023 prospective study of 353 children with acute otitis media found that twice-daily amoxicillin had similar efficacy to three-dose daily regimen (92% vs 95% favorable outcomes, p=0.25), but families reported fewer difficulties with the BD dosing schedule (31% difficulties with TDS vs 5.8% with BD) 5
Pharmacokinetic Rationale
A 2023 pooled population pharmacokinetic study of 261 neonates demonstrated that a twice-daily regimen of 50 mg/kg/day achieves adequate amoxicillin levels (50% time above MIC of 8 mg/L) and is superior to 3- or 4-times daily schedules in the first week of life 6
Oral bioavailability of amoxicillin in neonates is 87%, supporting the effectiveness of BD oral dosing 6
Practical Implementation
Age-Specific Dosing Algorithm
Infants <3 months: 30 mg/kg/day divided every 12 hours using 125 mg/5 mL suspension 1
Infants 3-12 months:
For a typical 6-month-old infant weighing 7 kg with pneumonia: 45 mg/kg/day = 315 mg/day = approximately 6.3 mL of 125/31 suspension twice daily 3, 7
Treatment Duration
Standard duration for respiratory infections is 7-10 days, with pneumonia specifically requiring 10 days 3, 4
Clinical improvement should be evident within 48-72 hours; if no improvement occurs, reevaluation is necessary 3, 4, 7
Common Pitfalls to Avoid
Never use TDS dosing when BD is available - this unnecessarily increases gastrointestinal side effects without improving efficacy 1, 8
Do not substitute different formulations without adjusting for clavulanate content - the 250/125 mg tablets contain different clavulanate ratios than 250/62.5 mg chewable tablets 1
Verify suspension concentration before dispensing - ensure families receive the correct 125/31 mg per 5 mL formulation for infants 3, 7
Administer at the start of meals - this enhances clavulanate absorption and minimizes gastrointestinal intolerance 1