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Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 2022 May 16;66(6):e02189-21. doi: 10.1128/aac.02189-21

Multicenter Population Pharmacokinetic Study of Unbound Ceftriaxone in Critically Ill Patients

Aaron J Heffernan a,b,, Fekade B Sime a, Nilesh Kumta a, Steven C Wallis a, Brett McWhinney c, Jacobus Ungerer c,d, Gloria Wong a, Gavin M Joynt f, Jeffrey Lipman a,e,g, Jason A Roberts a,g,h
PMCID: PMC9211414  PMID: 35575578

ABSTRACT

The objective of this study was to describe the total and unbound population pharmacokinetics of ceftriaxone in critically ill adult patients and to define optimized dosing regimens. Total and unbound ceftriaxone concentrations were obtained from two pharmacokinetic studies and from a therapeutic drug monitoring (TDM) program at a tertiary hospital intensive care unit. Population pharmacokinetic analysis and Monte Carlo simulations were used to assess the probability of achieving a free trough concentration/MIC ratio of ≥1 using Pmetrics for R. A total of 474 samples (267 total and 207 unbound) were available from 36 patients. A two-compartment model describing ceftriaxone-albumin binding with both nonrenal and renal elimination incorporating creatinine clearance to explain the between-patient variability best described the data. An albumin concentration of ≤20 g/L decreased the probability of target attainment (PTA) by up to 20% across different dosing regimens and simulated creatinine clearances. A ceftriaxone dose of 1 g twice daily is likely therapeutic in patients with creatinine clearance of <100 mL/min infected with susceptible isolates (PTA, ~90%). Higher doses administered as a continuous infusion (4 g/day) are needed in patients with augmented renal clearance (creatinine clearance, >130 mL/min) who are infected by pathogens with a MIC of ≥0.5 mg/L. The ceftriaxone dose should be based on the patient’s renal function and albumin concentration, as well as the isolate MIC. Hypoalbuminemia decreases the PTA in patients receiving intermittent dosing by up to 20%.

KEYWORDS: ceftriaxone, pharmacokinetics, dose, intensive care, intensive care unit, pharmacodynamics, population pharmacokinetics

INTRODUCTION

Antibiotic dose optimization in the critically ill patient is an important component of treatment that can influence patient outcomes (1, 2). For cephalosporins, concentrations that exceed the pathogen MIC throughout the dosing interval (i.e., minimum concentration at the end of the dosing interval [Cmin/MIC of >1]) are associated with 3-fold and 2-fold increases in clinical cure rates and bacterial eradication rates, respectively, compared to patients with lower exposures (35). A separate study has shown that achieving a β-lactam Cmin/MIC of ≥4.95 is associated with lower in-hospital mortality in patients with Gram-negative bacteremia (6). Such high blood exposures are consistent with the recommendations of some authors for use in patients with infections at sites where antibiotic penetration is low and/or variable, such as the epithelial lining fluid in pneumonia (79).

Achieving these pharmacokinetic/pharmacodynamic (PK/PD) targets can be particularly challenging in critically ill patients with acute physiological alterations that can manifest with hypoalbuminemia and augmented renal clearance (ARC), leading to altered antibiotic pharmacokinetics (10). Hypoalbuminemia can increase the unbound fraction of highly protein-bound drugs such as ceftriaxone, an antibiotic that is reported to have a variable unbound fraction of 5 to 17% (1013). Although a higher unbound fraction increases the pharmacologically active antibiotic available for antibacterial activity, antibiotic elimination may also be enhanced (1214). A serum albumin concentration of <25 g/L has previously been associated with a 25% increased ceftriaxone volume of distribution (V) compared with that of patients with a normal albumin concentration (40 g/L), affecting ≥40% of all patients admitted to the intensive care unit (ICU) (14, 15). An increased unbound fraction may also further increase ceftriaxone clearance in patients with ARC (creatinine clearance [CLCR] of ≥130 mL/min/1.73 m2), which may occur in 65.1% of patients (10, 11, 16).

A previous pharmacokinetic study conducted in critically ill patients admitted to the ICU showed that a 1-g twice-daily dose would likely achieve therapeutic exposures in most patients (17). However, this study did not investigate the impact of albumin concentration or ARC on selecting the optimal ceftriaxone dose for individual patients. The results of this study are consistent with other previous studies in critically ill patients admitted to the ICU, whereby 1-g or 2-g once-daily dosing regimens are unlikely to achieve an unbound Cmin/MIC of >1 (5, 1820).

The current study aims to describe the population pharmacokinetics of total and unbound ceftriaxone, incorporating any effects of albumin and creatinine clearance. A nonparametric pharmacokinetic modeling approach was used given the potential for improved parameter outlier detection, which may be common in critically ill patients given the highly variable physiological processes altering antibiotic pharmacokinetics (21). We sought to use the model to perform dosing simulations to determine optimized ceftriaxone doses for various patient scenarios that reliably achieve unbound trough concentrations exceeding a Cmin/MIC of >1 in adult patients, consistent with current therapeutic drug monitoring guidelines (2).

RESULTS

Study population.

A total of 474 (207 unbound paired samples and an additional 60 unpaired total concentration samples) ceftriaxone concentrations were available for 36 patients (Table 1). These patients had a mean age of 52 years, with hypoalbuminemia (mean, 23.9 g/L) and a normal creatinine clearance (median, 117.9 mL/min). Patients presented primarily with respiratory tract infections and received a 1-g twice-daily dose.

TABLE 1.

Patient demographic details

Parametera Result for parameter (n = 36)
Age, yr (IQR) 55.5 (39.0–61.3)
Female, n (%) 18 (48.7)
Wt, kg (IQR) 65 (59.5–80.0)
Albumin, g/L (IQR) 23 (20.0–28.3)
CLCR, mL/min (IQR) 104 (85–157.88)
Infection source, n (%)
 Intra-abdominal 6 (16.7)
 Respiratory 18 (50.0)
 Urinary tract 2 (5.6)
 Endovascular 2 (5.6)
 Central nervous system 6 (16.7)
 Prophylaxis extraventricular drain 2 (5.6)
Ceftriaxone dose administered
 1 g once daily 1
 2 g once daily 12
 1 g twice daily 17
 2 g twice daily 6
a

IQR, interquartile range.

Pharmacokinetic model.

The total and unbound ceftriaxone concentrations were adequately described using a two-compartment model with linear elimination and a complex protein binding model. Incorporating a complex ceftriaxone binding model improved the fit compared with a simple binding model when considering both a one-compartment model (Akaike information criterion [ΔAIC], −205; Bayesian information criterion [ΔBIC], −205) and two-compartment model (ΔAIC, −609; ΔBIC, −592) with linear elimination. A two-compartment complex binding model improved the model fit compared with a one-compartment complex binding model (ΔAIC, −378; ΔBIC, −369). The two-compartment model incorporating renal (TVR) and nonrenal (TVNR) ceftriaxone elimination improved the fit compared with renal elimination alone (ΔAIC, −55; ΔBIC, −51). Assuming that ceftriaxone may experience competitive binding with other molecules (i.e., the number of ceftriaxone molecules per albumin molecule may not equal 1), incorporating a variable binding number further improved the model fit (ΔAIC, −34; ΔBIC, −30). Incorporating creatinine clearance further improved the model fit (ΔAIC −42; ΔBIC, −41). The AIC and BIC values are included in Table 2. The incorporation of other covariates or power models did not improve the model fit. Therefore, the final clearance model is described by equation 1:

Ceftriaxone clearance = TVNR +(TVR ×CLCR118) (1)

TABLE 2.

Ceftriaxone pharmacokinetic model comparative log-likelihood in (2*LL), AIC, and BIC

Model description 2*LL AIC BIC
1 compartment
 Simple binding 3,958 3,966 3,982
 Complex binding 3,753 3,765 3,790
2 compartments
 Simple binding 3,958 3,970 3,995
 Complex binding 3,341 3,357 3,910
 Complex binding incorporating creatinine clearance 3,313 3,330 3,363
 Complex binding with 2 possible clearance routes 3,344 3,363 3,400
 Complex binding incorporating creatine clearance and nonrenal clearance 3,278 3,296 3,333

TVNR and TVR are the mean nonrenal and renal ceftriaxone clearance population values, respectively, and CLCR represents the creatinine clearance (in milliliters per minute). The final model differential equations are provided below, where equations 2, 3, and 4 describe the plasma unbound ceftriaxone concentration, the bound plasma ceftriaxone concentration, and the ceftriaxone concentration in the peripheral compartment, respectively:

dX1dt=doseCLV×X1KonV×(BmaxX2)×X1+Koff×X2Kcp×X1+Kpc×X3 (2)
dX2dt=KonV×(BmaxX2)×X1Koff×X2 (3)
dX3dt=Kcp×X1Kpc×X3 (4)

Kcp is the first-order constant for unbound ceftriaxone distribution from the central to peripheral compartment, Kpc is the first-order constant for unbound ceftriaxone distribution from the peripheral to central compartment. Other values have been defined in equations 5 to 7.

The final model was adequately fit as described by the visual predictive check for the unbound (Fig. 1) and total (Fig. 2) ceftriaxone concentrations. The unbound model population and individual predicted R2 values were 0.7 and 0.96, respectively (Fig. 3A and B, respectively). The total concentration model population and individual predicted R2 values were 0.83 and 0.97, respectively (Fig. 3C and D, respectively). The final model parameter estimates are described in Table 3. Model weighted residual error versus predicted and versus time are included in Fig. 4. Model parameter support points are detailed in Table S1 at https://doi.org/10.6084/m9.figshare.19614561.

FIG 1.

FIG 1

Observed unbound ceftriaxone concentration-time data and visual predictive check of the final model. Dots represent observed patient unbound ceftriaxone concentrations.

FIG 2.

FIG 2

Observed total concentration ceftriaxone concentration-time data and visual predictive check of the final model. Dots represent observed patient total ceftriaxone concentrations.

FIG 3.

FIG 3

Observed versus predicted goodness-of-fit plots for unbound and total ceftriaxone concentrations (open circles). (A) Population predicted unbound ceftriaxone concentration; (B) individual predicted unbound ceftriaxone concentration; (C) population predicted total ceftriaxone concentration; (D) individual predicted total ceftriaxone concentration. The ceftriaxone concentrations shown are milligrams per liter.

TABLE 3.

Ceftriaxone pharmacokinetic model parameter estimatesa

Parameter Mean (SD) Median 95% CI % RSE CV% Shrinkage (%)
TVNR (L/h) 7.27 (4.89) 6.86 5.73–8.77 11.21 67.29 7.79
TVR (L/h) 4.12 (5.47) 1.98 2.25–5.67 22.13 132.75 4.30
V (L) 7.43 (3.25) 7.25 6.45–8.33 7.29 43.66 18.50
Kon (L/mg/h) 1,290.19 (472.19) 1,312.04 1,169–1,412 6.10 36.60 27.56
Koff (h−1) 18,537.17 (4507.28) 18,961.57 17,177–19,916 4.05 24.32 17.95
Kcp (h−1) 4.00 (3.20) 3.04 3.15–4.89 13.33 80.01 24.15
Kpc (h−1) 0.65 (0.53) 0.48 0.49–0.80 13.59 81.23 16.97
N 0.82 (0.43) 0.69 0.69–0.94 8.74 51.71 21.84
a

95% CI, 95% bootstrapped confidence interval; TVNR, nonrenal ceftriaxone clearance; TVR, renal ceftriaxone clearance; V, volume of distribution; Kon, second-order association rate constant; Koff, first-order dissociation rate constant; Kcp, rate transfer constant from the central to peripheral compartment; Kpc, rate transfer constant from the peripheral to central compartment; N, number of ceftriaxone binding sites per albumin molecule; SD, standard deviation; RSE, residual squared error; CV, coefficient of variation.

FIG 4.

FIG 4

Residual diagnostic plots. (A) Weighted residual error versus predicted concentration; (B) weighted residual error versus time; (C) weighted residual error frequency histogram.

Dosing simulations.

The probability of target attainment (PTA) for the various ceftriaxone dosing regimens is presented in Table 4. Across the different dosing regimens and renal functions, lower albumin concentrations were associated with a reduced PTA. For each albumin reduction of 10 g/L, the PTA decreases at a given renal function by up to 20% (Table 4).

TABLE 4.

Probability of target attainment for an unbound ceftriaxone concentration Cmin/MIC of >1 over the first 24 h of therapya

Dose CLCR (mL/min) Albumin (g/L) Probability of achieving Cmin/MIC of >1
0.032 0.064 0.125 0.25 0.5 1 2 4 8
1 g q24h 40 20 1 1 1 0.98 0.86 0.61 0.33 0.11 0
40 30 1 1 1 1 0.91 0.70 0.39 0.12 0
40 40 1 1 1 1 0.94 0.77 0.42 0.12 0
100 20 1 1 0.97 0.88 0.67 0.32 0.10 0.03 0
100 30 1 1 1 0.94 0.79 0.50 0.13 0.03 0
100 40 1 1 1 0.98 0.86 0.58 0.17 0.03 0
160 20 0.99 0.97 0.9 0.73 0.36 0.13 0.07 0.02 0
160 30 1 0.99 0.96 0.84 0.59 0.20 0.08 0.02 0
160 40 1 1 0.98 0.91 0.72 0.31 0.09 0.02 0
2 g q24h 40 20 1 1 1 1 0.95 0.82 0.53 0.28 0.10
40 30 1 1 1 1 0.99 0.88 0.65 0.32 0.10
40 40 1 1 1 1 1 0.92 0.72 0.35 0.10
100 20 1 1 1 0.95 0.86 0.60 0.25 0.08 0.03
100 30 1 1 1 1 0.91 0.75 0.37 0.10 0.03
100 40 1 1 1 1 0.96 0.81 0.50 0.12 0.03
160 20 1 0.99 0.96 0.88 0.65 0.27 0.11 0.06 0.02
160 30 1 1 1 0.95 0.81 0.49 0.14 0.06 0.02
160 40 1 1 1 0.98 0.88 0.65 0.21 0.07 0.02
1 g q12h 40 20 1 1 1 1 0.99 0.94 0.76 0.40 0.07
40 30 1 1 1 1 0.99 0.97 0.78 0.39 0.05
40 40 1 1 1 1 1 0.98 0.79 0.35 0.03
100 20 1 1 1 1 0.97 0.86 0.62 0.15 0.01
100 30 1 1 1 1 0.99 0.88 0.68 0.17 0.01
100 40 1 1 1 1 1 0.93 0.71 0.15 0.01
160 20 1 1 1 0.99 0.92 0.76 0.33 0.07 0.01
160 30 1 1 1 1 0.96 0.80 0.46 0.07 0.01
160 40 1 1 1 1 0.97 0.83 0.52 0.07 0.01
2 g q12h 40 20 1 1 1 1 1 0.99 0.90 0.73 0.35
40 30 1 1 1 1 1 0.99 0.94 0.75 0.36
40 40 1 1 1 1 1 1 0.97 0.76 0.34
100 20 1 1 1 1 0.99 0.95 0.82 0.52 0.13
100 30 1 1 1 1 0.99 0.98 0.86 0.61 0.13
100 40 1 1 1 1 1 0.99 0.88 0.66 0.13
160 20 1 1 1 1 0.98 0.91 0.72 0.24 0.07
160 30 1 1 1 1 0.99 0.93 0.77 0.33 0.06
160 40 1 1 1 1 1 0.97 0.78 0.33 0.06
1 g q8h 40 20 1 1 1 1 1 0.97 0.85 0.61 0.17
40 30 1 1 1 1 1 0.98 0.88 0.61 0.12
40 40 1 1 1 1 1 0.99 0.89 0.55 0.09
100 20 1 1 1 1 0.99 0.94 0.78 0.41 0.05
100 30 1 1 1 1 1 0.96 0.80 0.41 0.04
100 40 1 1 1 1 1 0.97 0.81 0.35 0.04
160 20 1 1 1 1 0.98 0.88 0.71 0.17 0.03
160 30 1 1 1 1 0.99 0.92 0.75 0.19 0.03
160 40 1 1 1 1 1 0.95 0.77 0.19 0.02
2 g q8h 40 20 1 1 1 1 1 0.99 0.96 0.81 0.57
40 30 1 1 1 1 1 1 0.98 0.85 0.57
40 40 1 1 1 1 1 1 0.98 0.86 0.54
100 20 1 1 1 1 1 0.99 0.91 0.45 0.32
100 30 1 1 1 1 1 0.99 0.94 0.77 0.34
100 40 1 1 1 1 1 1 0.96 0.79 0.34
160 20 1 1 1 1 0.99 0.96 0.86 0.63 0.14
160 30 1 1 1 1 1 0.98 0.89 0.71 0.15
160 40 1 1 1 1 1 0.99 0.92 0.74 0.16
1-g LD + 2-g CI 40 20 1 1 1 1 1 1 1 0.96 0.72
40 30 1 1 1 1 1 1 1 0.96 0.66
40 40 1 1 1 1 1 1 1 0.96 0.52
100 20 1 1 1 1 1 1 1 0.89 0.52
100 30 1 1 1 1 1 1 1 0.88 0.49
100 40 1 1 1 1 1 1 1 0.87 0.39
160 20 1 1 1 1 1 1 0.98 0.82 0.26
160 30 1 1 1 1 1 1 0.98 0.82 0.26
160 40 1 1 1 1 1 1 0.98 0.82 0.23
1-g LD + 4-g CI 40 20 1 1 1 1 1 1 1 1 0.91
40 30 1 1 1 1 1 1 1 1 0.85
40 40 1 1 1 1 1 1 1 1 0.73
100 20 1 1 1 1 1 1 1 0.99 0.82
100 30 1 1 1 1 1 1 1 0.99 0.78
100 40 1 1 1 1 1 1 1 0.98 0.69
160 20 1 1 1 1 1 1 1 0.98 0.78
160 30 1 1 1 1 1 1 1 0.98 0.74
160 40 1 1 1 1 1 1 1 0.98 0.63
a

LD, loading dose; CI, continuous infusion; CLCR, creatinine clearance; q8h, q12h, and q24h, administered every 8, 12, and 24 h, respectively.

A 1-g once-daily dose should only be used if the MIC is low (≤0.125 mg/L) in patients with impaired renal function (creatinine clearance, <40 mL/min). In this population of patients with renal impairment (creatinine clearance, <40 mL/min), doses of 1 g twice-daily or 2 g once-daily are needed to ensure a PTA of >90% in patients infected with susceptible bacteria (MIC, ≤1 mg/L) (Table 4). Toxicity is unlikely (<1%) at this dose (Table 5). Patients with a creatinine clearance of 100 mL/min require a dose 1 g three times daily to ensure a PTA of >90% in susceptible bacteria (MIC, ≤1 mg/L), which is also associated with a probability of toxicity <1% (Table 5). Only high-dose (4 g/day) therapy administered in divided doses or as a continuous infusion has the potential to achieve the target fCmin/MIC >1 for susceptible isolates in >90% of patients with augmented renal clearance (22). Toxicity is unlikely in patients with augmented renal clearance (<1%), despite the high doses used in patients with augmented renal clearance. High-dose therapy (4 g/day) may result in toxicity for approximately 1.4% of patients with a creatinine clearance of <40 mL/min (Table 5).

TABLE 5.

Probability of toxicity within a 7-day treatment coursea

Dose CLCR (mL/min) Albumin (g/L) Probability of achieving total Cmin of >100 mg/L
1 g q24h 20 20 0
20 30 0
20 40 0
40 20 0
40 30 0
40 40 0
100 20 0
100 30 0
100 40 0
160 20 0
160 30 0
160 40 0
2 g q24h 20 20 0
20 30 0
20 40 0
40 20 0
40 30 0
40 40 0
100 20 0
100 30 0
100 40 0
160 20 0
160 30 0
160 40 0
1 g q12h 20 20 0
20 30 0
20 40 0
40 20 0
40 30 0
40 40 0
100 20 0
100 30 0
100 40 0
160 20 0
160 30 0
160 40 0
2 g q12h 20 20 0.01
20 30 0.01
20 40 0.01
40 20 0.01
40 30 0.01
40 40 0.01
100 20 0
100 30 0
100 40 0
160 20 0
160 30 0
160 40 0
1 g q8h 20 20 0.01
20 30 0.01
20 40 0.01
40 20 0
40 30 0
40 40 0
100 20 0
100 30 0
100 40 0
160 20 0
160 30 0
160 40 0
2 g q8h 20 20 0.06
20 30 0.06
20 40 0.06
40 20 0.01
40 30 0.01
40 40 0.01
100 20 0.01
100 30 0.01
100 40 0.01
160 20 0
160 30 0
160 40 0
1-g LD + 2-g CI 20 20 0
20 30 0
20 40 0
40 20 0
40 30 0
40 40 0
100 20 0
100 30 0
100 40 0
160 20 0
160 30 0
160 40 0
1-g LD + 4-g CI 20 20 0.03
20 30 0.03
20 40 0
40 20 0.01
40 30 0.01
40 40 0.01
100 20 0.01
100 30 0.01
100 40 0.01
160 20 0
160 30 0
160 40 0
a

LD, loading dose; CI, continuous infusion; CLCR, creatinine clearance; q8h, q12h, and q24h, administered every 8, 12, and 24 h, respectively.

When considering the fractional target attainment (FTA) for specific bacterial species, a 1-g twice-daily ceftriaxone dose is likely adequate in most patients who are infected with isolates other than Staphylococcus aureus (Table 6). Only high-dose continuous infusions of ceftriaxone (4 g/day) are likely to achieve a target exposure against S. aureus with a MIC of ≤4 mg/L for most patients.

TABLE 6.

Fractional target attainment for different ceftriaxone dosing regimens and bacterial speciesa

Dose CLCR (mL/min) Albumin (g/L) Fractional target attainment in:
E. coli H. influenzae K. pneumoniae S. pneumoniae S. aureus
1 g q24h 40 20 1 0.99 1 0.96 0.20
40 30 1 1 1 0.97 0.23
40 40 1 1 1 0.98 0.24
100 20 1 0.98 0.98 0.92 0.06
100 30 1 0.99 0.99 0.95 0.08
100 40 1 1 1 0.96 0.09
160 20 0.98 0.95 0.94 0.88 0.04
160 30 0.99 0.98 0.97 0.91 0.05
160 40 1 0.99 0.98 0.93 0.05
2 g q24 h 40 20 1 1 1 0.98 0.38
40 30 1 1 1 0.99 0.46
40 40 1 1 1 0.99 0.50
100 20 1 0.99 0.99 0.96 0.16
100 30 1 1 1 0.97 0.21
100 40 1 1 1 0.98 0.28
160 20 0.99 0.98 0.97 0.92 0.08
160 30 1 0.99 0.99 0.95 0.10
160 40 1 1 1 0.96 0.13
1 g q12h 40 20 1 1 1 0.99 0.54
40 30 1 1 1 0.99 0.55
40 40 1 1 1 1 0.52
100 20 1 1 1 0.99 0.34
100 30 1 1 1 0.99 0.38
100 40 1 1 1 0.99 0.38
160 20 1 1 1 0.97 0.18
160 30 1 1 1 0.98 0.23
160 40 1 1 1 0.98 0.26
2 g q12h 40 20 1 1 1 1 0.79
40 30 1 1 1 1 0.82
40 40 1 1 1 1 0.84
100 20 1 1 1 0.99 0.64
100 30 1 1 1 1 0.70
100 40 1 1 1 1 0.74
160 20 1 1 1 0.99 0.44
160 30 1 1 1 0.99 0.51
160 40 1 1 1 1 0.57
1 g q8h 40 20 1 1 1 1 0.70
40 30 1 1 1 1 0.71
40 40 1 1 1 1 0.68
100 20 1 1 1 0.99 0.55
100 30 1 1 1 1 0.56
100 40 1 1 1 1 0.54
160 20 1 1 1 0.99 0.39
160 30 1 1 1 0.99 0.42
160 40 1 1 1 1 0.43
2 g q8h 40 20 1 1 1 1 0.87
40 30 1 1 1 1 0.89
40 40 1 1 1 1 0.90
100 20 1 1 1 1 0.80
100 30 1 1 1 1 0.83
100 40 1 1 1 1 0.85
160 20 1 1 1 1 0.72
160 30 1 1 1 1 0.77
160 40 1 1 1 1 0.80
1-g LD + 2-g CI 40 20 1 1 1 1 0.97
40 30 1 1 1 1 0.98
40 40 1 1 1 1 0.97
100 20 1 1 1 1 0.92
100 30 1 1 1 1 0.92
100 40 1 1 1 1 0.91
160 20 1 1 1 1 0.87
160 30 1 1 1 1 0.87
160 40 1 1 1 1 0.87
1-g LD + 4-g CI 40 20 1 1 1 1 1
40 30 1 1 1 1 1
40 40 1 1 1 1 1
100 20 1 1 1 1 0.99
100 30 1 1 1 1 0.99
100 40 1 1 1 1 0.98
160 20 1 1 1 1 0.98
160 30 1 1 1 1 0.98
160 40 1 1 1 1 0.98
a

LD, loading dose; CI, continuous infusion; CLCR, creatinine clearance; q8, q12, and q24h, administered every 8, 12, and 24 h, respectively.

Dosing recommendations are provided in Table 7.

TABLE 7.

Dosing recommendations for susceptible isolates

CLCR (mL/min) Dosing recommendationa
≤60 1 g twice daily
61–139 1 g 3 times daily
≥140 1 g LD then 2–4 g CI or 2 g twice daily
a

Assuming a MIC of 1 mg/L and a PTA of ≥90%. Lower doses may be suitable for isolates with a MIC of <1 mg/L, depending on the patient’s clinical context.

DISCUSSION

The present study has demonstrated that the presence of ARC and hypoalbuminemia affects the ceftriaxone dosing requirements for critically ill patients. Overall, a 1-g twice-daily dose is likely to provide a target ceftriaxone exposure in most patients with a normal renal function and a highly susceptible isolate (MIC, ≤0.25 mg/L). Such a clinical scenario is likely to be commonly encountered based on the high FTA observed at lower ceftriaxone doses (1 g twice daily) for common bacterial species, even in patients with ARC. However, the dose may need to be increased to at least 3 g administered in divided intermittent doses (i.e., 1 g three times daily) or as a continuous infusion in patients infected with an isolate that has a MIC of ≥0.5 mg/L and/or in patients with ARC. A continuous infusion dosing regimen may improve the PTA in patients with hypoalbuminemia compared with intermittent dosing regimens. The PTA for ceftriaxone against methicillin-susceptible S. aureus (MSSA) is unfavorable due to the high clinical MIC susceptible breakpoint (≤8 mg/L, based on a wild-type distribution) compared with Enterobacterales (≤1 mg/L), and alternative treatment options should be considered.

Our volume of distribution estimates did not differ appreciably between critically ill patients and healthy study participants (19). Conversely, other studies in critically ill patients have identified an increased volume of distribution in critically ill patients compared with healthy participants (1719, 23, 24). The likely cause for such a discrepancy is the different modeling methods. Our study incorporated a ceftriaxone-albumin binding model, whereas previous studies have either only modeled the unbound ceftriaxone or extrapolated an unbound concentration from the total values, such as those by Schleibinger et al. (11) and Grégoire et al. (9). This is an important consideration as the unbound antibiotic concentration may not be reliably estimated using published values (12). A previous study has shown that such an approach is likely to overpredict the unbound ceftriaxone concentration by up to 83% (12). Furthermore, a calculated unbound concentration is unable to incorporate the inter- and intrapatient variability that may occur due to dynamic fluctuations in ceftriaxone and albumin concentrations. On the other hand, the total clearance in our study was comparable to those in studies previously conducted in patients admitted to the ICU (17, 18, 23, 24).

Despite the differences in the observed volume of distribution and clearance, our dosing recommendations are similar to those of previous studies. Schleibinger et al. recommended the use of a 2-g once-daily dose in patients with normal or impaired renal function, which may be appropriate for patients infected with highly susceptible organisms (MIC ≤0.125 mg/L) (11). On the other hand, patients with ARC require higher doses. Ollivier et al. identified that once-daily dosing is unlikely to achieve a Cmin/MIC of >1 in patients with ARC, who require a dose of 2 g twice daily, a finding similar to ours (23). Moreover, our simulations describe a similar dosing requirement to that previously proposed, despite a different modeling approach to describe the bound ceftriaxone concentration and the maximum ceftriaxone binding concentration (Bmax) (25). This pharmacokinetic study, similar to that conducted by Leegwater et al. (25), supports the use of administration by a continuous infusion to improve the PTA. Grégoire et al. recommend a ceftriaxone dose based on a nomogram considering both weight and renal function, which would also be approximately 2 g twice daily for a 70-kg patient with a creatinine clearance of 100 mL/min/1.73 m2 (9). Furthermore, a small clinical study of patients randomized to receive a 2-g once-daily dose or a 2-g continuous infusion observed an increased clinical cure rate in continuous infusion recipients controlling for confounding baseline factors (odds ratio, 22.8; 95% confidence interval, 2.24 to 232.3) (26). The use of a continuous infusion may be acceptable as ceftriaxone is stable in aqueous solutions at room temperature up to 48 h (27).

Clinicians must consider the infecting pathogen when selecting both the antibiotic agent and dose. Our pharmacokinetic study describing a low PTA of ceftriaxone against MSSA aligns with small clinical studies, whereby ceftriaxone therapy is associated with an increased risk of treatment failure for MSSA bacteremia compared with other therapy, such as cefazolin (54.5% failure for ceftriaxone versus 28.9% failure for cefazolin, P = 0.029) (28). Given the appreciable ceftriaxone concentration intra- and interpatient variability following standard dosing, therapeutic drug monitoring (TDM) may be appropriate to provide individualized dosing recommendations to improve the probability that target exposures are met and potentially improve patient outcomes (1, 2).

Although there are potential benefits of dose optimization, excessive ceftriaxone exposure may increase the risk of dose-related adverse events. In one study of patients receiving high-dose ceftriaxone for central nervous system infections, the risk of a suspected ceftriaxone adverse reaction was increased with total trough concentrations of ≥100 mg/L (odds ratio, 4.06; 95% confidence interval, 1.31 to 12.60), greatly exceeding the target exposure used for dosing simulations in our study (data not shown) (29). Furthermore, despite the use of such high doses, adverse events were uncommon, affecting 2.6% of patients. Such high exposures are unlikely to be encountered in patients when our dosing recommendations are followed. However, clinicians should monitor for changes in renal function that may necessitate dose reduction consistent with our recommendations.

Our study has several limitations. First, different ceftriaxone assays were used for the separate studies. Nonetheless, each assay methodology adhered strictly to regulatory standards, and meaningful systematic measurement errors are unlikely to have occurred. Second, other patient factors, such as illness severity or bilirubin concentrations, were not available for all patients to ascertain any impact these covariates may have on ceftriaxone pharmacokinetics (11). Third, the MIC distribution for specific isolates was obtained from the EUCAST MIC database, which may not generalize to all institutions. Fourth, the ceftriaxone concentrations were obtained in blood and not from the site of infection. Although this will describe the doses required to achieve the desired PK/PD target for patients with bacteremia, the doses described in this study may not provide a sufficient exposure in patients with other infection sites, such as the epithelial lining fluid for pneumonia (7). Nonetheless, the selection of a serum target of 100% time above the MIC (TMIC) may achieve the lowest likely effective exposure at the site of infection (60% fTMIC). Fifth, a calculated creatinine clearance measurement was available and is considered to be less accurate than a measured urinary creatinine clearance (30). However, this is also labor intensive, and the calculated creatinine clearance affords a practical bedside approach to improve dosing in critically ill patients. Sixth, there was a minority of patients with renal dysfunction, limiting the applicability of our findings in this patient population. Last, patient-centered outcomes such as mortality or toxicity were not assessed in this study—an important focus for future studies assessing ceftriaxone dosing regimens. Importantly, doses of >2 g daily should be used with caution in patients with renal dysfunction given the potential for adverse reactions such as seizures.

Conclusions.

Our study has highlighted the need for increased ceftriaxone doses to achieve a Cmin/MIC of >1 in critically ill patients with reduced albumin concentrations and/or increasing creatinine clearance. In patients with a normal creatinine clearance (~100 mL/min), a 1-g twice-daily dose is likely sufficient to achieve appropriate exposures in highly susceptible isolates (MIC, ≤0.25 mg/L). However, patients with ARC or those infected with a higher-MIC isolate (>0.25 mg/L) require a 3- to 4-g dose per day, either in divided doses or administered as a continuous infusion to achieve a Cmin/MIC of >1. Ceftriaxone should not be routinely used for the treatment of MSSA infections. Patients with ARC may benefit from TDM and early implementation of higher dosing regimens.

MATERIALS AND METHODS

Setting.

This study analyzed total and unbound ceftriaxone plasma concentrations obtained in three separate studies involving critically ill patients admitted to the ICU in two tertiary university hospitals—Royal Brisbane and Womens’ Hospital, University of Queensland, and Prince of Wales Hospital, Chinese University of Hong Kong. Data from a previous pharmacokinetic study with ceftriaxone conducted by Joynt et al. (17) (10 patients, Prince of Wales Hospital, Hong Kong) was combined with data obtained from a single-center therapeutic drug monitoring (TDM) program (31) conducted at the Royal Brisbane and Womens’ Hospital (17 patients) and a ceftriaxone pharmacokinetic study (nine patients) that included patients from both of the tertiary centers (Optimizing Antibiotic Cerebrospinal Fluid Exposures Study [OACES]). An ethics waiver was granted to use the TDM data that was performed as part of standard care. Ethical clearance was obtained for the OACES study (HREC/16/QRBW/157) and for the study by Joynt et al. as previously described (17).

Study population.

The study population and relevant inclusion/exclusion criteria for the patients included in the study by Joynt et al. have been previously described (17). For the OACES study, adult patients (age ≥18 years) admitted to the ICU receiving ceftriaxone intravenously for the treatment of sepsis with an extraventricular drain were eligible. Patients who were pregnant or receiving either intermittent or continuous hemodialysis were excluded. Clinical and anthropometric data, including the patient’s age (years), weight (kilograms), suspected infection source, microbiological results, albumin (grams per liter), and creatinine clearance (milliliters per minute) were extracted from the patient’s medical records, where available.

Sample handing, storage, and measurement.

Ceftriaxone concentration analysis was conducted as per the specific study site, although the methods were similar (17). The following unpublished method was performed for patients enrolled in the OACES study.

Unbound ceftriaxone was separated from plasma using a Centrifree device at 37°C prior to concurrent analysis as for a total ceftriaxone concentration. Samples were spiked with deuterated ceftriaxone as the internal standard, and proteins were precipitated using acetonitrile. Total and unbound ceftriaxone plasma concentrations were quantified using ultrahigh-pressure liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) on a Shimadzu Nexera device connected to a Shimadzu 8030+ triple quadrupole mass spectrometer. Briefly, chromatographic separation was achieved with an Xbridge C18 column (Waters, Milford, MA, USA) with a C18 guard column (Phenomenex, Torrance, CA, USA) using a mobile phase A consisting of ammonium formate (10 mM) at pH 1.5 adjusted with formic acid and mobile phase B of acetonitrile and 0.2% (vol/vol) formic acid. Ceftriaxone and the internal standard were detected using an electrospray source in positive mode optimized with multiple-reaction monitoring at fragmentation ions of 554.7→396.1 (sample ceftriaxone) and 557.7→399.10 (internal standard, deuterated ceftriaxone). Mean intrabatch accuracy and precision values were 4.4% and 9.4%.

Patients included from the TDM study had ceftriaxone concentrations analyzed using a previously validated and published methodology (32).

Population pharmacokinetic modeling.

Total and unbound ceftriaxone concentrations were comodeled using the Pmetrics version 1.5.2 software package for R (21). One- and two-compartment pharmacokinetic models were assessed incorporating linear elimination from the central compartment, as well as a linear intercompartmental distribution process for two-compartment models. Simple and complex ceftriaxone protein binding models were assessed as previously described by Byrne et al. (33). A simple binding model related the unbound ceftriaxone concentration to the total ceftriaxone concentration by equation 5:

Cfree=Cbound×FF×23Alb (5)

Alb is the albumin concentration (grams per liter), FF is the unbound free fraction, 23 is the mean albumin concentration (grams per liter), and Cfree and Cbound represent the unbound and bound ceftriaxone concentrations, respectively (milligrams per liter).

The complex binding model assumes ceftriaxone is solely bound to albumin and is described by equations 6, 7, and 8:

Cbound=Bmax×CfreeKD+Cfree (6)
Bmax=Alb×N×MCROMAlb×1,000 (7)
KD=1KA=KoffKon (8)

Cbound and Cfree represent the bound and unbound ceftriaxone concentrations (milligrams per liter), Bmax is the maximum ceftriaxone binding concentration (milligrams per liter), Alb is the concentration of albumin (grams per liter), N is the number of binding sites per albumin molecule, MCRO is the molecular weight of ceftriaxone, MAlb is the molecular weight of albumin, KD is the equilibrium dissociation rate constant (milligrams per liter), KA is the equilibrium affinity constant (liters per milligram), Koff is the first-order dissociation rate constant (per hour), and Kon is the second-order association rate constant (liters per milligram per hour).

For each model, the additive and multiplicative error models incorporating a linear residual error estimate within Pmetrics were assessed and optimized. Diagnostic plots, including the observed versus predicted concentrations, residuals versus predicted concentrations, and concentrations versus time, and the visual predictive plots, as well as the Akaike information criterion (AIC), Bayesian information criterion (BIC), and log-likelihood ratio (LLR), were considered to compare different models. Any reduction in the AIC or BIC was considered a potentially improved model, while a reduction in the LLR of ≥3.84 U was considered statistically significant when comparing nested models.

Patient variables were selected a priori for potential inclusion in the model to account for interpatient variability based on physiological plausibility. Variables assessed against the volume of distribution, intercompartmental clearance, nonrenal clearance, and renal clearance included age, sex, weight, creatinine clearance (determined using the Cockcroft-Gault equation using total body weight) (34), and serum albumin concentration. The incorporation of different patient variables into the model that reduced the LLR, AIC, or BIC and/or improved the goodness-of-fit plots were included.

Probability of target attainment and fractional target attainment.

Monte Carlo simulations (n = 1,000) were performed using ceftriaxone doses of 1 or 2 g administered every 8, 12, or 24 h (q8h, q12h, or q24h, respectively) as an intermittent dose or as a 1-g loading dose followed by a continuous infusion (2 and 4 g/day) in patients with a creatinine clearance ranging from 40 to 160 mL/min, with serum albumin concentrations of 20, 30, or 40 g/L. The probability of these regimens achieving an unbound ceftriaxone Cmin/MIC of >1 for MICs ranging from 0.032 to 8 mg/L was determined (22).

The fractional target attainment (FTA) represents the probability that patients would achieve the ceftriaxone PK/PD target against a specific pathogen assuming a wild-type distribution of MICs. The FTA, assuming an unbound ceftriaxone target of a Cmin/MIC of >1, was calculated for the above ceftriaxone dosing regimens for Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and methicillin-susceptible Staphylococcus aureus (MSSA) isolates, which are commonly implicated in severe community-acquired pneumonia and urosepsis infections. The MIC distribution for the bacterial species was obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) database (www.eucast.org), assuming 1 mg/L as the upper limit of susceptibility for isolates, with the exception of S. aureus, where the EUCAST epidemiological cutoff of 8 mg/L was used as the upper limit of susceptibility.

Dosing regimens were considered successful if the PTA was ≥90% of the simulated patient population. A dosing regimen was considered successful in treating a particular bacterial species if the FTA was ≥95%.

ACKNOWLEDGMENTS

Aaron J. Heffernan acknowledges funding from a Griffith School of Medicine Research Higher Degree scholarship, Fekade B. Sime acknowledges funding from a University of Queensland Postdoctoral Fellowship (W. T. Allen Bequest) and an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (APP1197866), and Jason A. Roberts acknowledges funding for an NHMRC Centre of Research Excellence (APP1099452) and a Practitioner Fellowship (APP1117065). No external funding was required for this study.

We declare no conflict of interest.

REFERENCES

  • 1.Scaglione F, Esposito S, Leone S, Lucini V, Pannacci M, Ma L, Drusano GL. 2009. Feedback dose alteration significantly affects probability of pathogen eradication in nosocomial pneumonia. Eur Resp J 34:394–400. 10.1183/09031936.00149508. [DOI] [PubMed] [Google Scholar]
  • 2.Abdul-Aziz MH, Alffenaar J-WC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, Neely MN, Paiva J-A, Pea F, Sjovall F, Timsit JF, Udy AA, Wicha SG, Zeitlinger M, De Waele JJ, Roberts JA, the Infection Section of European Society of Intensive Care Medicine (ESICM) . 2020. Antimicrobial therapeutic drug monitoring in critically ill adult patients: a position paper. Intensive Care Med 46:1127–1153. 10.1007/s00134-020-06050-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Craig WA. 1998. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–12. 10.1086/516284. [DOI] [PubMed] [Google Scholar]
  • 4.McKinnon PS, Paladino JA, Schentag JJ. 2008. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents 31:345–351. 10.1016/j.ijantimicag.2007.12.009. [DOI] [PubMed] [Google Scholar]
  • 5.Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, Kaukonen K-M, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Starr T, Wallis SC, Lipman J, Roberts JA, Lipman J, Starr T, Wallis SC, Paul SK, Margarit Ribas A, De Waele JJ, De Crop L, Spapen H, Wauters J, Dugernier T, Jorens P, Dapper I, De Backer D, Taccone FS, Rello J, Ruano L, Afonso E, Alvarez-Lerma F, Gracia-Arnillas MP, Fernandez F, Feijoo N, Bardolet N, Rovira A, Garro P, Colon D, Castillo C, Fernado J, Lopez MJ, Fernandez JL, Arribas AM, Teja JL, Ots E, Carlos Montejo J, Catalan M, et al. 2014. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 58:1072–1083. 10.1093/cid/ciu027. [DOI] [PubMed] [Google Scholar]
  • 6.Wong G, Taccone F, Villois P, Scheetz MH, Rhodes NJ, Briscoe S, McWhinney B, Nunez-Nunez M, Ungerer J, Lipman J, Roberts JA. 2020. β-Lactam pharmacodynamics in Gram-negative bloodstream infections in the critically ill. J Antimicrob Chemother 75:429–433. 10.1093/jac/dkz437. [DOI] [PubMed] [Google Scholar]
  • 7.Heffernan AJ, Sime FB, Lipman J, Dhanani J, Andrews K, Ellwood D, Grimwood K, Roberts JA. 2019. Intrapulmonary pharmacokinetics of antibiotics used to treat nosocomial pneumonia caused by Gram-negative bacilli: a systematic review. Int J Antimicrob Agents 53:234–245. 10.1016/j.ijantimicag.2018.11.011. [DOI] [PubMed] [Google Scholar]
  • 8.Heffernan AJ, Sime FB, Taccone FS, Roberts JA. 2018. How to optimize antibiotic pharmacokinetic/pharmacodynamics for Gram-negative infections in critically ill patients. Curr Opin Infect Dis 31:555–565. 10.1097/QCO.0000000000000494. [DOI] [PubMed] [Google Scholar]
  • 9.Grégoire M, Dailly E, Le Turnier P, Garot D, Guimard T, Bernard L, Tattevin P, Vandamme Y-M, Hoff J, Lemaitre F, Verdier M-C, Deslandes G, Bellouard R, Sébille V, Chiffoleau A, Boutoille D, Navas D, Asseray N. 2019. High-dose ceftriaxone for bacterial meningitis and optimization of administration scheme based on nomogram. Antimicrob Agents Chemother 63:e00634-19. 10.1128/AAC.00634-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, Hope WW, Farkas A, Neely MN, Schentag JJ, Drusano G, Frey OR, Theuretzbacher U, Kuti JL, International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases . 2014. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 14:498–509. 10.1016/S1473-3099(14)70036-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Schleibinger M, Steinbach CL, Töpper C, Kratzer A, Liebchen U, Kees F, Salzberger B, Kees MG. 2015. Protein binding characteristics and pharmacokinetics of ceftriaxone in intensive care unit patients. Br J Clin Pharmacol 80:525–533. 10.1111/bcp.12636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Wong G, Briscoe S, Adnan S, McWhinney B, Ungerer J, Lipman J, Roberts JA. 2013. Protein binding of β-lactam antibiotics in critically ill patients: can we successfully predict unbound concentrations? Antimicrob Agents Chemother 57:6165–6170. 10.1128/AAC.00951-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Ulldemolins M, Roberts JA, Rello J, Paterson DL, Lipman J. 2011. The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients. Clin Pharmacokinet 50:99–110. 10.2165/11539220-000000000-00000. [DOI] [PubMed] [Google Scholar]
  • 14.Finfer S, Bellomo R, McEvoy S, Lo SK, Myburgh J, Neal B, Norton R. 2006. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. Br Med J 333:1044. 10.1136/bmj.38985.398704.7C. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Mimoz O, Soreda S, Padoin C, Tod M, Petitjean O, Benhamou D. 2000. Ceftriaxone pharmacokinetics during iatrogenic hydroxyethyl starch-induced hypoalbuminemia: a model to explore the effects of decreased protein binding capacity on highly bound drugs. Anesthesiology 93:735–743. 10.1097/00000542-200009000-00023. [DOI] [PubMed] [Google Scholar]
  • 16.Udy AA, Baptista JP, Lim NL, Joynt GM, Jarrett P, Wockner L, Boots RJ, Lipman J. 2014. Augmented renal clearance in the ICU: results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations. Crit Care Med 42:520–527. 10.1097/CCM.0000000000000029. [DOI] [PubMed] [Google Scholar]
  • 17.Joynt GM, Lipman J, Gomersall CD, Young RJ, Wong ELY, Gin T. 2001. The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. J Antimicrob Chemother 47:421–429. 10.1093/jac/47.4.421. [DOI] [PubMed] [Google Scholar]
  • 18.Tsai D, Stewart P, Goud R, Gourley S, Hewagama S, Krishnaswamy S, Wallis SC, Lipman J, Roberts JA. 2016. Total and unbound ceftriaxone pharmacokinetics in critically ill Australian Indigenous patients with severe sepsis. Int J Antimicrob Agents 48:748–752. 10.1016/j.ijantimicag.2016.09.021. [DOI] [PubMed] [Google Scholar]
  • 19.Patel IH, Chen S, Parsonnet M, Hackman MR, Brooks MA, Konikoff J, Kaplan SA. 1981. Pharmacokinetics of ceftriaxone in humans. Antimicrob Agents Chemother 20:634–641. 10.1128/AAC.20.5.634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Pollock AA, Tee PE, Patel IH, Spicehandler J, Simberkoff MS, Rahal JJ, Jr.. 1982. Pharmacokinetic characteristics of intravenous ceftriaxone in normal adults. Antimicrob Agents Chemother 22:816–823. 10.1128/AAC.22.5.816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Neely MN, van Guilder MG, Yamada WM, Schumitzky A, Jelliffe RW. 2012. Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R. Ther Drug Monit 34:467–476. 10.1097/FTD.0b013e31825c4ba6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.The European Committee on Antimicrobial Susceptibility Testing. 2018. Breakpoint tables for interpretation of MICs and zone diameters. https://eucast.org. Accessed 14 January 2021.
  • 23.Ollivier J, Carrié C, d’Houdain N, Djabarouti S, Petit L, Xuereb F, Legeron R, Biais M, Breilh D. 2019. Are standard dosing regimens of ceftriaxone adapted for critically ill patients with augmented creatinine clearance? Antimicrob Agents Chemother 63:e02134-18. 10.1128/AAC.02134-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Garot D, Respaud R, Lanotte P, Simon N, Mercier E, Ehrmann S, Perrotin D, Dequin PF, Le Guellec C. 2011. Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal. Br J Clin Pharmacol 72:758–767. 10.1111/j.1365-2125.2011.04005.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Leegwater E, Kraaijenbrink BVC, Moes D, Purmer IM, Wilms EB. 2020. Population pharmacokinetics of ceftriaxone administered as continuous or intermittent infusion in critically ill patients. J Antimicrob Chemother 75:1554–1558. 10.1093/jac/dkaa067. [DOI] [PubMed] [Google Scholar]
  • 26.Roberts JA, Boots R, Rickard CM, Thomas P, Quinn J, Roberts DM, Richards B, Lipman J. 2007. Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study. J Antimicrob Chemother 59:285–291. 10.1093/jac/dkl478. [DOI] [PubMed] [Google Scholar]
  • 27.Herrera-Hidalgo L, Lopez-Cortes LE, Luque-Marquez R, Galvez-Acebal J, de Alarcon A, Lopez-Cortes LF, Gutierrez-Valencia A, Gil-Navarro MV. 2020. Ampicillin and ceftriaxone solution stability at different temperatures useful for outpatient parenteral antimicrobial therapy (OPAT). Antimicrob Agents Chemother 64:e00309-20. 10.1128/AAC.00309-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Carr DR, Stiefel U, Bonomo RA, Burant CJ, Sims SV. 2018. A comparison of cefazolin versus ceftriaxone for the treatment of methicillin-susceptible Staphylococcus aureus bacteremia in a tertiary care VA Medical Center. Open Forum Infect Dis 5:ofy089. 10.1093/ofid/ofy089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Le Turnier P, Navas D, Garot D, Guimard T, Bernard L, Tattevin P, Vandamme YM, Hoff J, Chiffoleau A, Dary M, Leclair-Visonneau L, Grégoire M, Pere M, Boutoille D, Sébille V, Dailly E, Asseray N, High-Dose Ceftriaxone CNS Infections Study Group . 2019. Is there a concentration threshold for ceftriaxone toxicity? Tolerability of high-dose ceftriaxone in CNS infections: a prospective multicentre cohort study. J Antimicrob Chemother 74:1078–1085. 10.1093/jac/dky553. [DOI] [PubMed] [Google Scholar]
  • 30.Ruiz S, Minville V, Asehnoune K, Virtos M, Georges B, Fourcade O, Conil JM. 2015. Screening of patients with augmented renal clearance in ICU: taking into account the CKD-EPI equation, the age, and the cause of admission. Ann Intensive Care 5:49. 10.1186/s13613-015-0090-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Wong G, Briscoe S, McWhinney B, Ally M, Ungerer J, Lipman J, Roberts JA. 2018. Therapeutic drug monitoring of β-lactam antibiotics in the critically ill: direct measurement of unbound drug concentrations to achieve appropriate drug exposures. J Antimicrob Chemother 73:3087–3094. 10.1093/jac/dky314. [DOI] [PubMed] [Google Scholar]
  • 32.Briscoe SE, McWhinney BC, Lipman J, Roberts JA, Ungerer JP. 2012. A method for determining the free (unbound) concentration of ten beta-lactam antibiotics in human plasma using high performance liquid chromatography with ultraviolet detection. J Chromatogr B Analyt Technol Biomed Life Sci 907:178–184. 10.1016/j.jchromb.2012.09.016. [DOI] [PubMed] [Google Scholar]
  • 33.Byrne CJ, Parton T, McWhinney B, Fennell JP, O'Byrne P, Deasy E, Egan S, Enright H, Desmond R, Ryder SA, D'Arcy DM, McHugh J, Roberts JA. 2018. Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in patients with haematological malignancy. J Antimicrob Chemother 73:995–1003. 10.1093/jac/dkx473. [DOI] [PubMed] [Google Scholar]
  • 34.Sunder S, Jayaraman R, Mahapatra HS, Sathi S, Ramanan V, Kanchi P, Gupta A, Daksh SK, Ram P. 2014. Estimation of renal function in the intensive care unit: the covert concepts brought to light. J Intensive Care 2:31. 10.1186/2052-0492-2-31. [DOI] [PMC free article] [PubMed] [Google Scholar]

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