Ceftolozane Tazobactam Pharmacokinetics in Infected Critically Ill Patients With an Indwelling External Ventricular Drain
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03309657|
Recruitment Status : Not yet recruiting
First Posted : October 13, 2017
Last Update Posted : October 13, 2017
Ceftolozane/tazobactam is an emerging newly available antibiotic that has a broad spectrum of activity, and could be potentially useful in the management of central nervous system infections. However, data relating to penetration of ceftolozane/ tazobactam into the central nervous system, where a barrier against drug distribution exists (i.e. blood brain barrier), is currently limited. In critically ill patients this is all the more challenging as achieving adequate antibiotic concentrations even in blood is difficult.
The aim of this study is to describe the concentrations achieved in the cerebrospinal fluid (i.e. bodily fluid found surrounding and inside of the brain) and blood after a single dose of ceftolozane/tazobactam administered in critically ill patients with an existing external ventricular drain (i.e. a device used in neurosurgery that relieves elevated intracranial pressure in the brain). It is planned that this information gained will help develop dosing strategies that will achieve target concentrations that will successfully treat central nervous system infections in the future.
|Condition or disease||Intervention/treatment||Phase|
|Pharmacokinetics||Drug: Ceftolozane/tazobactam||Phase 1 Phase 2|
Although relatively less frequent, Gram negative nosocomial meningitis and ventriculitis are observed in critical care settings, often associated with brain trauma, brain surgery, spinal fluid shunt after brain surgery, spinal abnormalities or severe urinary tract infections with bacteraemia. Gram negative meningitis is particularly challenging for treatment, when reduced susceptibility of some of the common etiologic bacteria is encountered (e.g. Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter aerogenes). Furthermore, the presence of the blood brain barrier (BBB) has meant that the choice of systemic antibiotics is very restricted due to the limited ability of many antibiotics to achieve adequate concentrations in the cerebrospinal fluid (CSF). The poor CSF penetration may also contribute to an accelerated rate of the emergence of resistant pathogens in some patients/units. A significant proportion of Gram negative bacilli clinical isolates (from patients with meningitis) are resistant to broad spectrum antibiotics such as the third or later generation cephalosporins. With the wide spread use of these antibiotics, the incidence of resistant nosocomial infections has increased. Thus, there is an acute need for novel antibiotics that can achieve adequate concentrations in the CSF, while exhibiting an excellent spectrum of activity.
Ceftolozane/tazobactam is an emerging newly available antibiotic that has a broad spectrum of activity, and could be potentially useful in the management of Gram negative meningitis. As compared to other commonly used beta lactam antibiotics, it exhibits superior antibacterial activity against difficult to treat Gram negative organisms, such as Pseudomonas aeruginosa and Enterobacteriaceae spp. It is relatively stable against various resistance mechanisms encountered by other beta lactams, and may be useful in the treatment of multi-drug resistant (MDR) infections. However, data relating to CSF penetration is limited. In the critically ill, achieving adequate antibiotic exposure, especially against the high MIC of some Gram negatives (e.g. Pseudomonas), is difficult even in plasma, let alone in CSF for which a distribution barrier (i.e. BBB) exists. Thus, it is prudent to investigate the CSF pharmacokinetics of this new drug before it is used 'off label' by clinicians without supportive data.
This study will describe the plasma and CSF pharmacokinetics of a 3.0 g dose of ceftolozane/tazobactam in critically ill patients with an indwelling external ventricular drain (EVD). We will use a population pharmacokinetics approach to determine if altered dosing or alternative modes of administration, such as prolonged infusion, should be considered to improve plasma exposure. Given that direct administration into the CSF (e.g. intraventricular route) is not only invasive but also may risk neurotoxicity, pharmacokinetic studies should explore the extent of drug distribution into CSF with systemic administration. There is no clinical data on the CSF penetration of ceftolozane/tazobactam in critically ill patients at the moment, and as such, this is a highly valuable study.
Aim of the study is to describe the pharmacokinetics of a single dose of ceftolozane/tazobactam in the plasma and CSF of critically ill patients with an indwelling EVD.
The study investigators hypothesise:
The plasma PK of cefolozane/tazobactam may be altered in critically ill patients with an indwelling EVD.
The distribution of ceftolozane/tazobactam into the CSF may be impaired by the blood brain barrier.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||10 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Open label pharmacokinetic study where enrolled critically ill patients with infection receive a single dose of ceftolozane-tazobactam (in addition to other active therapy).|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Ceftolozane Tazobactam Cerebrospinal Fluid Pharmacokinetics in Patients With External Ventricular Drains|
|Estimated Study Start Date :||October 2017|
|Estimated Primary Completion Date :||October 2019|
|Estimated Study Completion Date :||December 2020|
Experimental: Ceftolozane Tazobactam
Infected patients with external intraventricular drain will receive a single dose of Ceftolozane/ tazobactam (3000mg) over 1 hour and will undergo blood , csf and urine sampling at specific times over an 8 hour period.
IV ceftolozane 2000mg /tazobactam 1000mg once only
- Concentrations of a single dose of ceftolozane tazobactam in the plasma of critically ill patients with an indwelling external ventricular drain [ Time Frame: 24 hours ]- Measurement of Ceftolozane-Tazobactam concentrations (expressed as an area under the concentration-time curve) in the plasma of critically ill patients with an indwelling external ventricular drain.
- Concentrations of a single dose of ceftolozane tazobactam in the CSF of critically ill patients with an indwelling external ventricular drain [ Time Frame: 24 hours ]- Measurement of Ceftolozane-Tazobactam concentrations (expressed as an area under the concentration-time curve) in the CSF of critically ill patients with an indwelling external ventricular drain.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03309657
|Contact: Jason A Roberts, PhD BPharm||+61 7 email@example.com|
|Principal Investigator:||Jason A Roberts, PhD BPharm||Royal Brisbane and Womens Hospital|