What clinical evidence is there when comparing ceftriaxone 2 g q24h and ceftriaxone 1g IV q12h in patients with bacterial infections, such as pneumonia, or skin and soft tissue infections?

Comment by InpharmD Researcher

Limited clinical evidence comparing ceftriaxone 2 g every 24 hours and 1 g every 12 hours shows mixed results depending on the infection type. For community-acquired pneumonia (CAP), no significant efficacy or safety differences were found, though 1 g every 12 hours may have fewer side effects. In mild-to-moderate aspiration pneumonia, 2 g once daily improved early clinical responses and reduced inflammation while limiting adverse events. For pediatric bacterial meningitis, a 100 mg/kg once-daily regimen achieved better early target attainment in susceptible pathogens compared to twice-daily dosing, though neither regimen was effective against Staphylococcus aureus.

Background

A 2024 population pharmacokinetic (PK) analysis developed a serum–cerebrospinal fluid (CSF) model to assess the distribution, penetration, and pharmacodynamic performance of once- or twice-daily ceftriaxone in children treated empirically for bacterial meningitis. The investigators prospectively obtained 103 samples (16 serum and 87 CSF) from 98 pediatric patients aged between 0.1 and 18.5 years at a tertiary referral hospital. Inclusion was limited to opportunistically collected remnant clinical samples. Using the developed model, ceftriaxone regimens of 100 mg/kg once daily (OD) and 50 mg/kg twice daily (BD) were simulated in 1000 virtual pediatric patients to compare CSF pharmacodynamic target attainment (PTA) across time. For susceptible pathogens with a minimum inhibitory concentration (MIC) of 1 mg/L, such as Streptococcus pneumoniae and Haemophilus influenzae, the once-daily regimen achieved superior early target attainment, with an 88% PTA from 2.5 to 24 hours post-initiation, compared to 53% with twice-daily dosing. Both regimens reached 100% PTA at steady-state intervals (72–96 h and 168–192 h). For Staphylococcus aureus, with an MIC of 4 mg/L, neither regimen achieved adequate CSF target concentrations—PTAs remained below 75% even at late time points (168–192 h). These findings align with the 2024 European Committee on Antimicrobial Susceptibility Testing (EUCAST) MIC breakpoints and provide pharmacometric support for favoring 100 mg/kg once daily ceftriaxone regimens in empirical meningitis management, while also highlighting the inadequacy of ceftriaxone monotherapy in S. aureus meningitis. [1]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What clinical evidence is there when comparing ceftriaxone 2 g every 24 hours and ceftriaxone 1g IV every 12 hours in patients with bacterial infections such as pneumonia, or skin and soft tissue infections

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Comparative prospective cohort study of efficacy and safety according to dosage and administration of ceftriaxone for community-acquired pneumonia
Design	Prospective cohort study N= 457
Objective	To compare initial treatment failure, 30-day mortality, and side effects between two groups of hospitalized adult community-acquired pneumonia (CAP) patients receiving intravenous ceftriaxone at 1g twice daily (1g Q12 hr) and 2g once daily (2g Q24 hr)
Study Groups	1g Q12 hr (n= 186) 2g Q24 hr (n= 271)
Inclusion Criteria	Hospitalized CAP patients from a Japanese hospital treated with intravenous ceftriaxone at 1g Q12 hr or 2g Q24 hr
Exclusion Criteria	Patients younger than 15 years, using antibiotics other than ceftriaxone, dosages and administrations other than specified, those with antimicrobial therapy started before admission, and those with nursing and healthcare-associated pneumonia (NHCAP), healthcare pneumonia (HCAP), or hospital-associated pneumonia (HAP)
Methods	Patients were treated with intravenous ceftriaxone at either 1g twice daily or 2g once daily. Inverse probability of treatment weighting (IPTW) analysis was used to minimize biases.
Duration	Treated between October 2010 to December 2018
Outcome Measures	Primary: Initial treatment failure Secondary: 30-day mortality, frequency of side effects
Baseline Characteristics	Characteristic	1g Q12 hr (n= 186)	2g Q24 hr (n= 271)
	Age (IQR), years	76 (70–84)	77 (69–83)
	Male	127 (68.3%)	185 (68.3%)
	Smoking history	120 (64.5%)	169 (62.4%)
	Chronic heart disease	66 (35.5%)	74 (27.3%)
	COPD	59 (31.7%)	76 (28.0%)
	Asthma	36 (19.4%)	34 (12.5%)
	Diabetes mellitus	41 (22.0%)	48 (17.7%)
	Most common causative pathogen S.pneumoniae H.influenzae Unknown	18.3% 15.1% 53.8%	24.0% 12.2% 55.7%
Results	Outcome	1g Q12 hr (n= 186)	2g Q24 hr (n= 271)	HR, 95% CI; p-value
	Initial treatment failure	2.43%	4.46%	0.542, 0.18 to 1.60; 0.27
	30-day mortality	2.95%	6.43%	0.441, 0.15 to 1.26; 0.13
	Side effects Drug fever Liver dysfunction Drug-induced pneumonia C. Difficile infection	1.04% 1 (0.54%) 1 (0.54%) 0 0	4.20% 4 (1.48%) 6 (2.21%) 1 (0.37%) 1 (0.37%)	0.239, 0.05 to 1.16; 0.08 - - - -
	CI, confidence interval; HR, hazard ratio
Adverse Events	See above
Study Author Conclusions	No significant difference was found between ceftriaxone 1g Q12 hr and 2g Q24 hr regarding efficacy or safety in adult patients with CAP. However, ceftriaxone 1g Q12 hr may represent a safer option in terms of side effects.
Critique	The study's prospective design and use of IPTW analysis are strengths, providing a robust comparison of dosing regimens. However, the single-center design and exclusion of minor adverse events limit generalizability. The study did not directly determine the equivalence of different dosages, and the sample size may not have been large enough to detect small differences in side effects.

References:

Nakanishi Y, Ito A, Tachibana H, Kawataki M, Ishida T. Comparative prospective cohort study of efficacy and safety according to dosage and administration of ceftriaxone for community-acquired pneumonia. J Infect Chemother. 2025;31(1):102516. doi:10.1016/j.jiac.2024.09.005

Retrospective Comparison of the Effectiveness and Safety of Ceftriaxone 1 g Twice Daily versus 2 g Once Daily for Treatment of Aspiration Pneumonia
Design	Retrospective, single-center study N= 61
Objective	To evaluate the effectiveness and safety of 1 g twice daily versus 2 g once daily administration of ceftriaxone in adult patients with aspiration pneumonia
Study Groups	1 g twice daily (n= 33) 2 g once daily (n= 28)
Inclusion Criteria	Patients receiving ceftriaxone for the treatment of aspiration pneumonia from January 2015 to September 2021
Exclusion Criteria	Patients <15 years old, receiving ceftriaxone for <2 days, or with lung abscesses
Methods	Retrospective review of medical records. Patients were divided into two groups based on dosing regimens: 1 g twice daily or 2 g once daily. Clinical responses, inflammatory markers, and adverse events were evaluated.
Duration	January 2015 to September 2021
Outcome Measures	Clinical success rate (achieving clinical cure and improvement), body temperature < 37.0°C, CRP < 60% of baseline, survival rate
Baseline Characteristics	Characteristic	1 g twice daily (n= 33)	2 g once daily (n= 28)
	Age, years	73 (17–90)	72 (41–86)
	Body weight, kg	55.8 (36.8–103.6)	52.9 (29.0–81.1)
	Duration of therapy, days	6 (3–17)	6 (3–15)
Results	Endpoint	1 g twice daily (n= 33)	2 g once daily (n= 28)	p-value
	Clinical success	84.8%	100%	0.0316
	Body temperature < 37.0°C	45.5%	78.3%	0.0141
	CRP < 60%	25.0%	60.7%	0.0051
	Survival rate	93.9%	100%	0.1853
Adverse Events	The incidence of choleliths was higher in the 1 g twice daily group (31.3%) compared to the 2 g once daily group (9.1%), though not statistically significant (p = 0.174)
Study Author Conclusions	A 2 g once daily administration of ceftriaxone improved clinical responses and reduced inflammatory markers early in patients with mild-to-moderate aspiration pneumonia, while limiting adverse events.
Critique	The study's retrospective design and small sample size limit the generalizability of the findings. The lack of randomization and potential for selection bias are additional limitations.

References:

Kato H, Hagihara M, Morikawa Y, Asai N, Mikamo H, Iwamoto T. Retrospective Comparison of the Effectiveness and Safety of Ceftriaxone 1 g Twice Daily versus 2 g Once Daily for Treatment of Aspiration Pneumonia. Antibiotics (Basel). 2022;11(8):983. Published 2022 Jul 22. doi:10.3390/antibiotics11080983