Ceftriaxone dosing: 1, 2, 3 or 4 grams daily?

Moving between countries can challenge your clinical practice. In Belgium, I was used to giving ceftriaxone as a 2 grams once daily dose (with some exceptions like meningitis or Gonococcal infections). In Australia, however, most patients receive ceftriaxone 1 gram twice daily, although pneumonia is still treated with ceftriaxone 2 gram once daily.

This difference in clinical practice poses some interesting questions:

1. Which factors play a role in determining the dosing of ceftriaxone?

2. What is the standard dose of ceftriaxone: 1 or 2 grams once daily, or 1 gram twice daily?

3. In which situations might more than 2 gram of ceftriaxone be beneficial?

1. Which factors play a role in determining the dose of ceftriaxone?

Ceftriaxone is a third generation cephalosporin, commonly used to treat urinary tract infections, community-acquired pneumonia and intra-abdominal infections all around the world. As a beta-lactam antibiotic, the main determinant of efficacy is time above the minimal inhibitory concentration (MIC). Surprisingly, the optimal pharmacodynamic target remains undefined (2). The existing literature mentions most often the following targets:

1. Unbound concentration of ceftriaxone > MIC for 60 to 70% of the dosing interval (2,3)

2. Unbound concentration of ceftriaxone > MIC for 100% of the dosing interval (2-4).

Theoretically, it makes sense to aim for a higher target to achieve adequate antibiotic penetration at the site of infection. For instance, the concentration of beta-lactams at the epithelial lining fluid is only 20% of the plasma concentration (5). Moreover, some studies have shown that a concentration of ceftriaxone above MIC throughout the dosing interval leads to an improved microbiological and clinical cure(4).

3. Unbound concentration of ceftriaxone > 4-fold higher than MIC for 100% of the dosing interval (6).In critically ill patients, aiming for a higher pharmacokinetic/pharmacodynamic target (PK/PD) might be indicated, as tissue penetration of ceftriaxone will be even more restricted, by, for instance, alterations in the microcirculation during septic shock (2). One study in gram-negative bacteremia demonstrated that applying such target for beta-lactam antibiotics in general resulted in an increased survival (4).

To achieve the pharmacodynamic target of ceftriaxone, the subsequent pharmacokinetic factors might play a role:

* Dosing interval: More frequent dosing results in a higher average concentration of ceftriaxone. One small, randomized controlled trial even suggested that continuous infusion of ceftriaxone might lead to an improved clinical and microbiological cure rate (13), compared to intermittent dosing. This finding would be consistent with other PK/PD studies in beta-lactam antibiotics (1).

* Albumin level: Ceftriaxone is highly protein bound, which explains its longer half-life. Only the unbound fraction is biologically active. A higher unbound fraction, as seen in critically ill patients or in cases of hypoalbuminemia, leads to a faster elimination of the drug and potentially under-exposure. Some observational studies have suggested that hypoalbuminemia may lead to lower rates of clinical success (7). However, these studies intrinsically have a confounding bias, as hypoalbuminemia itself is also associated with increased mortality. Multiple pharmacokinetic models have demonstrated that hypoalbuminemia does have an effect. However, this is not clinically relevant (4,6) as long as albumin is higher than 19.6 g/L and ceftriaxone dose is at least 2 grams daily.

* Body weight: This remains a topic of debate. Some authors suggest adapting ceftriaxone to body weight, especially in case of meningitis (8). By contrast, another model found weight to have a statistically significant but clinically irrelevant predictive value (6).

* Elimination: Ceftriaxone is eliminated 40% through the bile ducts and 60% unchanged in the urine. Variations in renal function might have a major impact on the PK/PD target attainment for ceftriaxone. While a dose of 1 gram is sufficient in patients on renal replacement therapy (2), up to 4 grams may be required in case of augmented renal clearance (creatinine clearance exceeding 100 mL/min) (4,6).

2. What is the standard dose of ceftriaxone: 1 or 2 grams once daily, or 1 gram twice daily?

The optimal dose of ceftriaxone is still a subject of debate. For example, the World Health Organization Collaborating Centre for Drug Statistics Methodology has defined this as a daily dose of 2 grams (9) whereas the Sanford Guide to Antimicrobial Therapy recommends 1 to 2 grams daily (10).

No direct comparison between a dosing regimen of 1 and 2 grams ceftriaxone in a randomized controlled trial has ever been conducted. The limited evidence available is far from conclusive.

• A meta-analysis compared 24 randomized controlled trials in community-acquired pneumonia, where one arm of these studies included ceftriaxone 1 gram, 2 grams once daily, or 1 gram twice daily. In a modified intention to treat analysis, no statistically significant difference was seen in mortality between ceftriaxone 1 and 2 grams. However, this meta-analysis has many methodological limitations (9).

  
  

• Retrospective cohort studies in community-acquired pneumonia and intra-abdominal infections showed no difference between 1 and 2 grams ceftriaxone daily (10-12). In all these studies, the choice of dosing ceftriaxone was at the physician’s discretion (with the standard dose being 1 gram daily), raising concern about the potential bias in these results.

  
  

• Apart from the economic cost, a dose of 2 grams has no major side effects compared to a 1-gram dose. Theoretically, there is an increased risk of gallstones with higher doses (10). Moreover, one study observed a slightly higher incidence of C. difficile infections (however still only 0.6%) (12).

  
  

• A single-center prospective observational study measured the unbound trough concentration of ceftriaxone in non-critically ill, septic patients in the emergency department. This concluded that 1 gram of ceftriaxone per day was insufficient to achieve therapeutic concentration in over 90% of cases (5).

  
  

• A pharmacokinetic model predicts that 1 gram of ceftriaxone twice daily provides better coverage than 2 grams once daily in case of augmented renal clearance or higher MIC. However, a head-to-head comparison between these dosing regimens is lacking (4).

My view: No definitive recommendation can be made due to insufficient data. However, I would stick with a daily dose of 2 grams ceftriaxone as it carries minimal additional side effects. In contrast, 1 gram ceftriaxone could risk underdosing, a scenario you absolutely want to avoid. Pharmacokinetically, 1 gram twice daily appears superior but 2 grams once daily might be sufficient for non-critically ill patients.

3. In which situations might more than 2 grams of ceftriaxone be beneficial?

1) Critically ill patients, especially in case of augmented renal clearance.

As mentioned before, ceftriaxone is eliminated more rapidly in case of augmented renal clearance, which can result in underdosing. For instance, one model projected achieving minimal concentration > MIC in only 88% of cases if the creatinine clearance was more than 100 ml/min and ceftriaxone was given as 1 gram twice daily. This increased to 98% with a dose of 2 grams twice daily (4). Another model also concluded that 2 grams twice daily might be beneficial in case of augmented renal clearance (6).

2) Bacterial meningitis

Traditionally, bacterial meningitis is already treated with ceftriaxone 2 grams twice daily. However, with augmented renal clearance, this dose may be insufficient, particularly within the cerebrospinal fluid (8). For this reason, French guidelines recommend ceftriaxone 100 mg/kg/day, without maximum dose, as empirical therapy in case of acute bacterial meningitis (14).

References:

1. Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis. JAMA. 2024 Aug 27;332(8):638-648.

 2. Ulldemolins M, Bastida C, Llauradó-Serra M, et al. Once-daily 1 g ceftriaxone optimizes exposure in patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration. Eur J Clin Pharmacol. 2021 Aug;77(8):1169-1180.

 3. Garot D, Respaud R, Lanotte P, et al. Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal. Br J Clin Pharmacol. 2011 Nov;72(5):758-67.

 4. Heffernan AJ, Sime FB, Kumta N, et al. Multicenter Population Pharmacokinetic Study of Unbound Ceftriaxone in Critically Ill Patients. Antimicrob Agents Chemother. 2022 Jun 21;66(6):e0218921.

 5. Heffernan AJ, Curran RA, Denny KJ, et al. Ceftriaxone dosing in patients admitted from the emergency department with sepsis. Eur J Clin Pharmacol. 2021 Feb;77(2):207-214.

 6. Dreesen E, Gijsen M, Elkayal O, et al. Ceftriaxone dosing based on the predicted probability of augmented renal clearance in critically ill patients with pneumonia. J Antimicrob Chemother. 2022 Aug 25;77(9):2479-2488.

 7. Arensman Hannan K, Draper E, Cole KC, et al. Impact of hypoalbuminemia on clinical outcomes among patients with obesity treated with ceftriaxone. Antimicrob Agents Chemother. 2024 Apr 3;68(4):e0166323.

 8. Grégoire M, Dailly E, Le Turnier P, et al. High-Dose Ceftriaxone for Bacterial Meningitis and Optimization of Administration Scheme Based on Nomogram. Antimicrob Agents Chemother. 2019 Aug 23;63(9):e00634-19.

 9. Telles JP, Cieslinski J, Gasparetto J, et al. Efficacy of Ceftriaxone 1 g daily Versus 2 g daily for The Treatment of Community-Acquired Pneumonia: A Systematic Review with Meta-Analysis. Expert Rev Anti Infect Ther. 2019 Jul;17(7):501-510.

 10. Hasegawa S, Sada R, Yaegashi M, et al. 1g versus 2 g daily intravenous ceftriaxone in the treatment of community onset pneumonia - a propensity score analysis of data from a Japanese multicenter registry. BMC Infect Dis. 2019 Dec 26;19(1):1079.

 11. Zequinão T, Ross FS, Marinho GDT, et al. Ceftriaxone 1 g versus 2 g per day, for the treatment of community-acquired pneumonia: a retrospective cohort study-comment. Intern Emerg Med. 2025 Jan;20(1):329-332.

 12. Guz D, McNeil R, Buchrits S, et al. Ceftriaxone 1 g versus 2 g per day, for the treatment of community-acquired pneumonia: a retrospective cohort study. Intern Emerg Med. 2023 Oct;18(7):1919-1927.

 13. Roberts JA, Boots R, Rickard CM, et al. Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study. J Antimicrob Chemother. 2007 Feb;59(2):285-91.

 14. Le Turnier P, Tattevin P, Varon E, et al. Empirical Treatment in Acute Bacterial Meningitis: a Plea for High Doses of Cefotaxime or Ceftriaxone. Antimicrob Agents Chemother. 2023 Apr 18;67(4):e0001223.