None listed
Conditions
Brief summary
The primary aim of this study is to compare the effects of two approaches to the administration of beta-lactam antibiotics (continuous infusion and intermittent bolus dosing) on ICU-free days up to Day 28, with dosing at clinician discretion and independent of randomisation group. The null hypothesis is that there is no difference in ICU-free days up to Day 28 between patients assigned to continuous infusion and those assigned to standard bolus dosing.
Interventions
In critically ill patients with severe sepsis, how does continuous beta-lactam infusion compared with intermittent beta-lactam bolus dosing affect ICU-free days up to Day 28?Beta-lactam antibiotics are the class of antibiotics most commonly used to treat infection in patients with severe sepsis. In a recent point prevalence study of antibiotic usage in Australia and New Zealand conducted in conjunction with the Extended Study on Prevalence of Infection in Intensive Care (EPIC II), among ICU pati
In critically ill patients with severe sepsis, how does continuous beta-lactam infusion compared with intermittent beta-lactam bolus dosing affect ICU-free days up to Day 28?Beta-lactam antibiotics are the class of antibiotics most commonly used to treat infection in patients with severe sepsis. In a recent point prevalence study of antibiotic usage in Australia and New Zealand conducted in conjunction with the Extended Study on Prevalence of Infection in Intensive Care (EPIC II), among ICU patients being treated for infection, 4 of the 5 most commonly used antibiotics were beta-lactams. The three most commonly prescribed beta-lactams were ticarcillin-clavulanate (23% of all antibiotics), meropenem (20% of all antibiotics), and piperacillin-tazobactam (13% of all antibiotics). Routine use of continuous infusions for beta-lactam administration was extremely low; with a point prevalence estimate of 1.8% for all beta-lactam antibiotics used in Australian and New Zealand ICUs. The theoretical rationale for administration of beta-lactams via continuous infusion is well recognised. Bacterial killing is related to the duration of time that bacteria are exposed to a concentration of antibiotic that exceeds the Minimum Inhibitory Concentration (MIC). It is well established that administration of beta-lactam antibiotics by infusion produces higher blood and tissue serum levels. While continuous infusion is superior to bolus administration in animal and in vitro models of infection in the absence of an effective immune response, two meta-analyses of the human trials conducted to date have not demonstrated that continuous infusion is superior to intermittent administration in terms of clinical cure and survival. These human trials, however, have been underpowered, even when pooled, and primarily conducted in non-critically ill patients. In addition, 13 of the 14 studies included in the meta-analysis by Roberts et al. used higher doses in the intermittent arm. The beta-lactam antibiotic chosen by the treating physician will be randomised to continuous infusion or intermittent bolus administration. The dose and dosing interval of the antibiotic will be chosen by the treating physician so as to reflect body size and estimated drug clearance. The dose of antibiotic will be the same regardless of treatment group allocation and antibiotic dosing can be modified during the study based on predicted or actual changes to renal clearance. Dosing will continue as per clinician's discretion, ICU discharge or to a maximum of 14 days.
Sponsors
NHMRC
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion criteria: 1. Confirmed or suspected infection with new organ dysfunction, based on established entry criteria for severe sepsis 2. The treating clinician has chosen ticarcillin-clavulanate, meropenem or piperacillin-tazobactam to treat the episode of infection in Criterion 1. 3. The treating clinician is uncertain if administration of the chosen antibiotic by bolus administration or by infusion is superior. 4. At the time of the assessment of suitability for the study, the treating ICU specialist expects the patient will require treatment in the ICU that extends beyond the next calendar day. Organ Dysfunction Entry Criteria: The patient must meet one or more the following organ dysfunction entry criteria in the previous 24 hours: 1. Cardiovascular (shock): An arterial systolic blood pressure (SBP) of equal to 90 mmHg or a mean arterial pressure (MAP) equal to 70 mmHg for at least one hour despite adequate fluid resuscitation or adequate intravascular volume status (as previously defined), and/or need for vasopressors to achieve a SBP or MAP target (as specified by the treating physician) for greater than one hour. Vasopressors are defined as: a) Dopamine greater than 5 micro g/kg/min b) Noradrenaline, adrenaline, metaraminol or phenylephrine by infusion at any dose. 2. Renal: Acute kidney injury with serum creatinine greater than 1.5 x hospital admission creatinine or less than 0.5 ml/kg/hour for 6 hours. A patient with loss of kidney function or end-stage kidney disease (defined as the need for renal replacement therapy for more than 4 weeks or the need for dialysis for longer than 3 months) would need to meet one of the other organ failure criteria. 3. Respiratory: Respiratory failure defined as PaO2/FiO2 equal to 200. 4. Haematology: Platelet count of less than 80 x 109/L or a greater than 50% decrease in the platelet count from the highest recorded value within the preceding 3 days. 5. Metabolic acidosis: Defined by one of the following: a) pH less than 7.30 b) Base deficit greater than 5.0 mmol/L c) A venous or arterial plasma lactate level greater than 1.5 times the upper limit of normal for the reporting laboratory.
Exclusion criteria
Patients meeting one or more of the following criteria are to be excluded: 1. Receipt of any potential study drug for more than 24 hours prior to randomisation during this admission to the ICU 2. Age less than 18 years 3. Allergy or potential allergy to the study medications 4. Pregnancy 5. No central venous catheter access with three or more lumens 6. Receiving palliative or supportive treatment only at the time of assessment for eligibility 7. Treating physician is not committed to provision of advanced life-support including any of mechanical ventilation, dialysis, and vasopressor administration for at least the next 48 hours 8. Death is deemed imminent and inevitable 9. The patient has an underlying process that is likely to result in death before 90 days of follow up. 10. Consent has not been gained for study participation.
Outcome results
None listed