Once-Daily Alternative to Ampicillin
Ceftriaxone is the preferred once-daily alternative to ampicillin, dosed at 2 g IV/IM once daily for adults or 50-100 mg/kg/day (maximum 4 g) for pediatric patients, depending on the indication. 1, 2
Rationale for Ceftriaxone as First-Line Alternative
Ceftriaxone offers convenient once-daily dosing with equivalent or superior efficacy compared to ampicillin for most indications where ampicillin is traditionally used 1, 3
The American Heart Association explicitly recommends ceftriaxone as an alternative to ampicillin for endocarditis treatment, noting that "ampicillin 2 g IV every 4 h is a reasonable alternative to penicillin if a penicillin shortage exists," but ceftriaxone can be given once daily instead 1
For prosthetic valve endocarditis caused by viridans group streptococci, ceftriaxone 2 g/24 h IV or IM in 1 dose for 6 weeks is recommended as equivalent to ampicillin given every 4 hours 1
Dosing Recommendations
Adults
- Standard dose: 2 g IV once daily for most infections 1, 2
- For endocarditis: 2 g IV every 12 hours OR 4 g IV once daily (maximum daily dose) 2
- For HACEK endocarditis: 2 g IV/IM once daily for 4 weeks (native valve) or 6 weeks (prosthetic valve) 2
Pediatric Patients
- General dosing: 50-75 mg/kg/day for less severe infections, 50-100 mg/kg/day for severe infections (maximum 4 g daily) 4
- For endocarditis: 100 mg/kg/day divided every 12 hours OR 80 mg/kg/day every 24 hours (up to 4 g daily) 2, 4
- For meningitis: 100 mg/kg/day (maximum 4 g daily), with once-daily dosing showing superior CSF penetration compared to twice-daily dosing 4, 5
Clinical Evidence Supporting Superiority
In bacterial peritonitis, ceftriaxone 1 g plus metronidazole once daily was significantly more effective than ampicillin-based regimens, with wound infection rates of 6% versus 19% (p = 0.02) 3
Ceftriaxone achieves better tissue penetration and longer duration of therapeutic levels due to its extended half-life, making it ideal for outpatient parenteral antibiotic therapy (OPAT) 2, 6
Important Caveats
For Enterococcus faecalis endocarditis, the once-daily high-dose ceftriaxone regimen (4 g) may not maintain adequate synergistic concentrations throughout the 24-hour dosing interval when combined with ampicillin, with only 0% of patients maintaining target levels at 24 hours 6
Intramuscular injection of ceftriaxone is painful and should be avoided when possible, preferring IV administration 2
Dosing adjustments are required in severe renal impairment, though specific guidelines vary by indication 2
Alternative Once-Daily Options (Second-Line)
Amoxicillin-Clavulanate
- Not truly once-daily for most indications, as standard dosing is 875/125 mg twice daily for adults 7
- Less convenient than ceftriaxone and requires multiple daily doses for adequate coverage 7
Ampicillin-Sulbactam
- Requires dosing every 6-8 hours, not once-daily 8
- Not a suitable alternative for once-daily dosing despite broad spectrum activity 8
Bottom line: Ceftriaxone is the definitive once-daily alternative to ampicillin for nearly all indications, with the exception of E. faecalis endocarditis where twice-daily dosing may be preferable to maintain synergistic concentrations. 1, 2, 6