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JAC Advance Access originally published online on November 28, 2006
Journal of Antimicrobial Chemotherapy 2007 59(2):285-291; doi:10.1093/jac/dkl478
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study

Jason A. Roberts1,2, Rob Boots1,2, Claire M. Rickard3, Peter Thomas1, Jo Quinn1, Darren M. Roberts1, Brent Richards4 and Jeffrey Lipman1,2,*

1 Royal Brisbane and Women's Hospital, Brisbane Australia 2 Burns Trauma and Critical Care Research Centre, University of Queensland Brisbane, Australia 3 Monash University Melbourne, Australia 4 Gold Coast Hospital Gold Coast, Australia

*Correspondence address. Burns Trauma and Critical Care Research Centre, Level 3, Ned Hanlon Building, Royal Brisbane and Women's Hospital, Butterfield Street, Herston, Queensland, 4029, Australia. Tel: +61-736361852; Fax: +61-736363542; E-mail: j.lipman{at}uq.edu.au

Received 16 August 2006; returned 14 September 2006; accepted 30 October 2006


   Abstract
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Objectives: To compare the clinical and bacteriological outcome of critically ill patients with sepsis treated by ceftriaxone administered as a once-a-day intermittent bolus dose or by 24 h continuous infusion.

Patients and methods: We conducted an open-label, randomized controlled pilot study in 57 patients clinically diagnosed with sepsis (suspected/proven infection and systemic inflammatory response syndrome) in a tertiary level intensive care unit. Patients were randomized to receive 2 g of ceftriaxone administered by once-daily intermittent bolus dosing or by 24 h continuous infusion. Clinical and bacteriological outcomes were assessed by blinded clinicians.

Results: Fifty-seven patients were enrolled in the study, 50 of whom fulfilled the a priori definition of treatment for 4 or more days. The infusion (n = 29) and bolus groups (n = 28) were similar in terms of demographics, although the median age of those receiving the infusion was younger. Intention-to-treat analysis found no statistically significant differences in the primary outcomes for clinical response (P = 0.17), clinical cure [infusion n = 13/29 versus bolus n = 5/28; adjusted odds ratio (AOR) = 3.74; 95% confidence interval (95% CI) = 1.11–12.57; P = 0.06], bacteriological response (P = 0.41) and bacteriological cure (infusion n = 18/29 versus bolus 14/28; AOR = 1.64; 95% CI = 0.57–4.70; P = 0.52). However, logistic regression in patients that complied with the a priori definitions who received ceftriaxone by continuous infusion (AOR = 22.8; 95% CI = 2.24–232.3; P = 0.008) or patients with a low Acute Physiology and Chronic Health Evaluation (APACHE) II score (AOR = 0.70; 95% CI = 0.54–0.91; P = 0.008) were associated with an improved clinical outcome when age and Sepsis Organ Failure Assessment (SOFA) score at time of study entry were controlled for.

Conclusions: This pilot study suggests clinical and bacteriological advantages of continuous infusion of ceftriaxone over bolus administration in critically ill patients in patients requiring 4 or more days of treatment. This sets the scene for a large multicentre double-blind randomized controlled trial to confirm these findings.

Keywords: ß-lactams , antibiotics , sepsis , outcome


   Introduction
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The treatment of sepsis1 remains a significant challenge to critical care physicians worldwide with persisting high mortality and morbidity rates. Compelling evidence suggests that with source control of the pathogen, early and appropriate antibiotic therapy remains the most effective intervention available to clinicians for such patients.2–6 It follows that optimizing empirical antibiotic therapy should therefore be a priority in the management of patients with sepsis.

Typical drug dosage regimens are based on data from healthy volunteers. However, this may be problematic for critically ill patients with sepsis who may have clinically important altered drug clearances and/or volumes of distribution.7–13 Such pharmacokinetic variability may affect antibiotic concentrations at the site of infection. For time-dependent (or concentration-independent) bacterial killing antibiotics such as ß-lactams, such variability can lead to prolonged periods where antibiotic concentrations fall below the MIC for the infective pathogen. Compelling pharmacokinetic and pharmacodynamic data exist recommending continuous infusion of ß-lactams to minimize this possibility.7,14–20 There is however, limited outcome data to support the perceived clinical and bacteriological advantages of continuous ß-lactam infusions.14,21 Two recent meta-analyses have articulated the need for randomized controlled trials (RCTs) that measure these proposed advantages.21,22

The third-generation cephalosporin ceftriaxone has broad-spectrum activity against many clinically relevant bacteria encountered in the critically ill. Unlike most ß-lactams, ceftriaxone has an extended half-life (t1/2; 5.8–8.7 h) and as such the manufacturer, in line with other clinical studies, recommends a once-daily intravenous administration regimen.23–25 However, ceftriaxone has been shown to have altered pharmacokinetics in critically ill patients with normal renal function with clearance increasing up to 100% and volume of distribution by up to 90%.26 Joynt et al.26 have shown previously that this may cause ceftriaxone concentrations to fall below the MIC for extended periods of time. This may lead to impaired bacteriological activity and sub-optimal patient outcomes. Furthermore, we have anecdotally observed a trend towards twice-daily dosing, which further highlights the uncertainty of clinicians as to appropriate prescribing of this antibiotic.

This pilot study aimed to compare the clinical and bacteriological outcome of critically ill patients, diagnosed with sepsis and treated with 2 g of ceftriaxone administered by once-daily bolus dosing or by 24 h continuous infusion.


   Patients and methods
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This study was performed in an 18 bed general tertiary referral intensive care unit (ICU). Patients were enrolled where ceftriaxone was deemed appropriate empirical therapy by the treating critical care physician using criteria outlined in Table 1.


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  		Table 1. Inclusion and exclusion criteria

 
The primary endpoints of the study were clinical cure and bacteriological cure. Secondary endpoints were measured as ventilator days and mortality.

Randomization

Patients were randomized into two groups—bolus administration or continuous infusion, using sequential opaque sealed envelopes (sequence generated from a table of random numbers) which were opened by the treating physician after consent was gained from the patient or legally authorized representative (Figure 1).


Figure 1
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  		Figure 1. CONSORT randomization flow chart.

 
Intervention

Subjects in the bolus arm received 2 g administered once a day, and those in the infusion arm received 2 g as a 24 h infusion. To rapidly target adequate antibiotic levels in the infusion group, a 500 mg loading dose of ceftriaxone was given by bolus injection at the initiation of antibiotic therapy. To make the two groups comparable, a 500 mg bolus was also given to the bolus group (2.5 g bolus day 1). All subsequent management including addition of other antibiotics was at the treating physician's discretion.

Data collection

Data for analysis included patient demographics, admission diagnosis, concomitant antibiotic therapy, progress and outcome, daily organ system failures and Sepsis Organ Failure Assessment (SOFA) scores,27 Acute Physiology and Chronic Health Evaluation (APACHE) II score28 on admission to ICU plus at the time of entry to the trial, full blood count, serum biochemistry including liver function tests, arterial blood gases and coagulation studies as per standard practice in the ICU. Analysis of data was primarily performed on an intention-to-treat (ITT) basis. However, as this was a pilot study, a priori, we also elected to analyse patients that received at least 4 days of antibiotic therapy. This analysis intended to remove potential confounding subjects that may not have required empirical antibiotic therapy or were moribund. This principle has also been adopted by previous studies.14,20 Clinical and bacteriological outcomes were assessed at the cessation of ceftriaxone treatment by a critical care physician blinded to the groupings and with no role in the management of the subjects. Patients were enrolled in the study until discharge or death. Detailed clinical and microbiological data were collected while the patient was being treated with ceftriaxone as per study protocol.

Outcome definitions

The definitions for the primary outcomes are detailed in Table 2.


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  		Table 2. Patient outcome definitions

 
Microbiology

Microbiological specimens were collected as part of standard ICU care. Susceptibility to relevant antibiotics were tested by disc-diffusion, broth or agar dilution techniques according to CLSI (formerly NCCLS) standards and with American Type Culture Collection (ATCC) control strains.29 Microbiological specimens were graded categorically.

Statistical analysis

Statistical analysis was performed on all demographic parameters to compare groups using STATA 7TM (College Station, TX, USA). A P value <0.05 was considered significant for all statistical tests. Student's t-tests, Mann–Whitney U-tests and {chi}2 tests were used where appropriate. Where univariate analysis showed an association at P ≤ 0.2, forward stepwise logistic regression for the relationship between outcome and demographic variables was used. Where appropriate, Fisher's exact test was used for non-parametric data. Data are reported as adjusted odds ratio (AOR); 95% confidence interval (95% CI); P value.

Ethics approval

Ethics approval for research was granted from the local institutional research and ethics committee.


   Results
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 Abstract
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Discussion
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Intention-to-treat analysis

Fifty-seven patients consented and were randomized (infusion group n = 29 and bolus group n = 28). The patient demographics are shown in Table 3. Length of ICU and hospital admission were both shorter for the bolus group although this trend was not statistically significant. This may be due to one outlier in the infusion group who was admitted to ICU for 122 days and hospital for 350 days but only required 5 days of ceftriaxone treatment.


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  		Table 3. Patient demographics of randomized patients

 
Using ITT analysis the bolus and infusion groups were not significantly different in terms of clinical response (P = 0.08), clinical cure (AOR = 3.74; 95% CI = 1.11–12.57; P = 0.06), bacteriological response (P = 0.41), bacteriological cure (AOR = 1.64; 95% CI = 0.57–4.70; P = 0.52) or mortality (AOR = 0.48; 95% CI = 0.47–0.64; P = 0.25).

A priori analysis (patients that received 4 or more days of ceftriaxone therapy)

Seven of the recruited patients did not receive at least 4 days of ceftriaxone therapy and were not included in the subgroup analysis. The demographic, clinical and treatment characteristics of the patients excluded from a priori analysis are described in Table 4.


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  		Table 4. Patients a priori deemed not evaluable who received <4 days of ceftriaxone therapy (n = 7)

 
The isolated bacterial pathogens are detailed in Table 5. Fourteen patients did not have an organism isolated immediately before, or during, their ceftriaxone course of treatment (seven patients receiving bolus administration and seven patients receiving continuous administration). Thirteen patients had two organisms isolated and one patient had three organisms isolated. Table 6 details patient outcomes. Logistic regressions for clinical cure and bacteriological cure were both controlled for age and SOFA score at the time of study entry.


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  		Table 5. Clinical pathogens

 


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  		Table 6. Patient outcomes to ceftriaxone treatment

 
Three patients failed ceftriaxone treatment, two in the bolus group and one in the infusion group. In the bolus group, one of these patients yielded H. influenzae (MIC 0.003 mg/L for ceftriaxone) and an S. aureus (MIC 4 mg/L—for which concomitant vancomycin therapy was included). The other bolus patient yielded a Streptococcus pneumoniae (MIC < 0.025 mg/L for ceftriaxone). The infusion failure was moribund on admission and deceased on day 3 of treatment. No organisms were isolated for this patient. The clinical outcomes of the other patients classified as failures were not assessable and were included as failures to be conservative.

Neither group was associated with an increased incidence of adverse effects as measured by renal failure and clinical observation by the treating physician.

Concomitant antibiotic therapy

Forty-three (of 57 enrolled) patients received concomitant antibiotics during ceftriaxone therapy of whom 19 patients received more than one additional antibiotic. There was no statistical difference in the number of antibiotics used between the infusion and bolus groups (P = 0.66) and sub-analyses were not possible given the small numbers of individual antibiotics.


   Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Conclusions
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 References
 
The ITT analysis of this cohort found no statistically significant differences between the infusion and bolus groups in any of the primary (clinical and bacteriological cure) or secondary endpoints (ventilator days and mortality). The ITT analysis included some patients with less severe illness and patients that were moribund and it is for this reason that a priori we also chose to analyse patients that received 4 or more days of ceftriaxone therapy. This subgroup of the cohort did provide some data suggesting clinical and bacteriological advantages of continuous infusion of ceftriaxone compared with bolus administration in critically ill patients. This provides some additional data to support the in vitro, pharmacokinetic and pharmacodynamic studies that promote continuous infusion of ß-lactam antibiotics.7,14–20,30 However, validation of such approaches requires larger RCTs to quantify both clinical and bacteriological efficacy and to determine the precise indication for continuous infusions of ß-lactam antibiotics in the critically ill.7,14,21

The effect of the lower age of the infusion group (P = 0.04) on clinical cure in patients receiving 4 or more days of therapy remains unknown. Age is unlikely to have confounded the results as it was not found to be predictive of bacteriological resolution or eradication.

Logistic regression modelling, found a low APACHE II score to be predictive of resolution of infection in patients receiving 4 or more days of therapy (Table 7). While previous studies have also correlated positive clinical outcomes with low APACHE II scores,31–33 no studies could be found in the literature that also purport statistically significant bacteriological advantages. It follows that this result should be confirmed by a larger study.


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  		Table 7. Logistic regression models for resolution of clinical illness and bacterial eradication for patients receiving at least 4 days of ceftriaxone treatment

 
We calculated that a sample size of 560 patients would be required in each group in a subsequent trial to detect the 8% difference in the bacteriological outcomes of ‘eradicated’ or ‘presumed eradicated’ found in this study with a type I error of 5% and a type II error of 20%. This supports the ITT analysis of this pilot study which showed no difference between the groups in either clinical or bacteriological outcome, possibly due to the small cohort enrolled, which required the collapsing of definitions into smaller groups for further analysis. Furthermore, only patients who provided informed consent were included in this study which is only a portion of eligible patients admitted to our ICU. This limitation may reduce the generalizability of the conclusions of the study.

Four previous RCTs could be found in the literature that compare continuous infusion and bolus administration of a ß-lactam antibiotic. Lau et al.34 (n = 262, piperacillin/tazobactam), Georges et al.14 (n = 50, cefepime), Hanes et al.35 (n = 31, ceftazidime) and Nicolau et al.20 (n = 35, ceftazidime) all showed equivalence between continuous infusion and bolus administration in the clinical and/or bacteriological outcomes measured. These studies, along with two subsequent meta-analyses,21,22 identify that administration of ß-lactam antibiotics by either continuous infusion or bolus administration produces at least equivalent clinical and bacteriological results. These data indicate that continuous infusion is not inferior to bolus administration but the clinical benefit of continuous infusion is yet to be proven.

However, unlike the above studies, our study has provided some data on the possible clinical and bacteriological advantages associated with continuous infusion of a ß-lactam antibiotic in critically ill patients receiving 4 or more days of therapy. This difference may have emerged because in conducting this pilot study, in addition to the ITT analysis, we elected a priori to compare outcomes for patients who received at least 4 days of therapy, with no other mandatory antibiotic therapy. Receiving at least 4 days of therapy may enable differences between continuous and bolus administration to become evident. While Georges et al.14 and Nicolau et al.20 also required a minimum antibiotic treatment duration (5 days), participants were co-administered an aminoglycoside which may have reduced any potential differences between both modes of administration. Hanes et al.35 required no minimum duration of treatment. Furthermore, Georges et al.14 did not administer a loading dose and along with Nicolau et al.20 and Hanes et al.35 used lower doses in the continuous infusion groups. Lau et al.34 administered the same dose to both groups and required patients to be treated for at least 4 days. The largest of these studies was by Lau et al., and the authors concluded continuous infusion to be a safe and reasonable alternate mode of dosing to bolus administration.

Suffice to say, the clinical and bacteriological data presented in this paper provide impetus for a large multicentre double-blind RCT to further investigate these findings. It was beyond the aims of this research project to measure any pharmacokinetic data because of the numerous pharmacokinetic and pharmacodynamic data that already exist.7,14–20


   Conclusions
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusions
Transparency declarations
 References
 
This pilot study provides some data that suggest clinical and bacteriological advantages of continuous infusion of ceftriaxone over bolus administration in critically ill patients diagnosed with sepsis. Improvement in the primary endpoints of clinical and bacteriological cure was evident for patients receiving continuous infusions of ceftriaxone for 4 or more days but not in the ITT analysis. Secondary endpoints showed no difference in mortality or ventilator days. These results are indeed an interesting addition to the argument purporting the greater clinical use of continuous infusion of ß-lactam antibiotics and set the scene for a large multicentre double-blind RCT to confirm these findings.


   Transparency declarations
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References
 
None to declare.


   Acknowledgements
 
This research was performed at the Intensive Care Units at the Royal Brisbane and Women's Hospital, Brisbane, Australia and Gold Coast Hospital, Gold Coast, Australia. We would like to recognize the contribution of Mandy Tallott for recruiting patients to this study. J. A. R. and D. M. R. acknowledge the support of the National Health and Medical Research Council (Australia). Declaration of financial support: institutional department funds.


   References
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 Abstract
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 Patients and methods
 Results
 Discussion
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 Transparency declarations
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1 Bone RC, Balk RA, Cerra FB, et al. (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644–55.

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14 Georges B, Conil JM, Cougot P, et al. (2005) Cefepime in critically ill patients: continuous infusion vs. an intermittent dosing regimen. Int J Clin Pharmacol Ther 43:360–9.[Web of Science][Medline]

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16 Angus BJ, Smith MD, Suputtamongkol Y, et al. (2000) Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis. Br J Clin Pharmacol 50:184–91.[Medline]

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19 Lipman J, Gomersall CD, Gin T, et al. (1999) Continuous infusion ceftazidime in intensive care: a randomized controlled trial. J Antimicrob Chemother 43:309–11.[Abstract/Free Full Text]

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26 Joynt GM, Lipman J, Gomersall CD, et al. (2001) The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. J Antimicrob Chemother 47:421–29.[Abstract/Free Full Text]

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34 Lau WK, Mercer D, Itani KM, et al. (2006) Randomized, open-label, comparative study of piperacillin-tazobactam administered by continuous infusion versus intermittent infusion for treatment of hospitalized patients with complicated intra-abdominal infection. Antimicrob Agents Chemother 50:3556–61.[Abstract/Free Full Text]

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