What is the preferred dosing regimen, twice daily (BD) or three times daily (TID), for intravenous (IV) antibiotics, such as amoxicillin?

BD vs TID Dosing for IV Antibiotics

For IV antibiotics, dosing frequency should be determined by the specific agent's pharmacokinetics and the infection being treated, with most guidelines recommending QID (every 6 hours) or TDS (every 8 hours) for beta-lactams like ampicillin and penicillin, while ceftriaxone uniquely allows for once or twice daily dosing due to its extended half-life. 1

Beta-Lactam Antibiotics (Ampicillin, Penicillin, Nafcillin, Oxacillin)

These agents require more frequent dosing (QID or every 4-6 hours) due to their short half-lives and time-dependent killing:

• Ampicillin IV: 200-300 mg/kg/day divided every 4-6 hours for serious infections including sepsis and meningitis 1
• Penicillin G IV: 200,000-300,000 U/kg/day divided every 4 hours for endocarditis and serious streptococcal infections 1
• Nafcillin/Oxacillin IV: 200 mg/kg/day divided every 4-6 hours for staphylococcal infections 1
• Cefazolin IV: 100 mg/kg/day divided every 8 hours (TDS) for staphylococcal skin and soft tissue infections 1

The rationale is that beta-lactams exhibit time-dependent bacterial killing, requiring serum concentrations above the minimum inhibitory concentration (MIC) for 40-70% of the dosing interval. 1

Ceftriaxone: The Exception

Ceftriaxone is the only commonly used IV antibiotic that can be dosed once or twice daily:

• 100 mg/kg/day IV divided every 12 hours OR 80 mg/kg/day IV every 24 hours for most infections 1
• This flexibility is due to ceftriaxone's extended half-life (approximately 8 hours) and high protein binding 1

Aminoglycosides (Gentamicin, Tobramycin)

These agents are typically dosed once daily in adults but may require divided dosing in children:

• Gentamicin: 3-6 mg/kg/day IV divided every 8 hours in children; adults receive 3-5 mg/kg/day once daily 1
• Once-daily dosing exploits concentration-dependent killing and post-antibiotic effect while potentially reducing nephrotoxicity 1

Vancomycin

Vancomycin requires divided dosing due to its pharmacokinetic profile:

• Pediatric: 40 mg/kg/day IV divided every 8-12 hours (up to 60 mg/kg/day for endocarditis) 1
• Adult: 30 mg/kg/day in 2 divided doses (BD), with dose adjustments based on trough levels 1

Carbapenems and Extended-Spectrum Agents

These require TDS or QID dosing:

• Meropenem: 1 g every 8 hours IV in adults; 20 mg/kg/dose every 8 hours in children 1
• Piperacillin-tazobactam: 3.37 g every 6-8 hours IV in adults 1
• Ceftazidime: 100-150 mg/kg/day divided every 8 hours for Pseudomonas coverage 1

Critical Considerations

Common pitfalls to avoid:

• Never extend dosing intervals for time-dependent antibiotics (penicillins, cephalosporins except ceftriaxone, carbapenems) beyond recommended intervals, as this compromises efficacy 1
• For serious infections like endocarditis, meningitis, and necrotizing fasciitis, strict adherence to QID or TDS dosing is essential for optimal outcomes 1
• Aminoglycoside dosing in children differs from adults—children typically require divided dosing (every 8 hours) rather than once-daily dosing 1

Oral Amoxicillin/Clavulanate Context

While the question asks about IV dosing, it's worth noting that oral amoxicillin-clavulanate has been successfully reformulated for BD dosing (875/125 mg twice daily) with equivalent efficacy to TDS regimens 2, 3, 4. This was achieved by increasing the amoxicillin component while maintaining adequate clavulanate levels. 3 However, this principle does NOT apply to IV beta-lactams, which still require more frequent dosing. 1

Compliance studies demonstrate that BD regimens achieve 84.5% adherence versus 72.7% for TDS regimens 5, but this advantage is irrelevant for hospitalized patients receiving IV antibiotics under direct medical supervision. 5, 6