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Ceftolozane Tazobactam Pharmacokinetics in Infected Critically Ill Patients With an Indwelling External Ventricular Drain

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ClinicalTrials.gov Identifier: NCT03309657
Recruitment Status : Not yet recruiting
First Posted : October 13, 2017
Last Update Posted : October 13, 2017
Sponsor:
Collaborator:
The University of Queensland
Information provided by (Responsible Party):
Royal Brisbane and Women's Hospital

Brief Summary:

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

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
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

Resource links provided by the National Library of Medicine

Drug Information available for: Tazobactam

Arm Intervention/treatment
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.
Drug: Ceftolozane/tazobactam
IV ceftolozane 2000mg /tazobactam 1000mg once only




Primary Outcome Measures :
  1. 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.

  2. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients with any infection requiring treatment with ceftolozane/tazobactam and who have met the following criteria:

  • Age >18 years
  • The presence of an indwelling external ventricular drain (EVD) or requiring EVD insertion due to obstructive hydrocephalus/subarachnoid haemorrhage

Exclusion Criteria:

  • Known or suspected allergy to penicillins and cephalosporins
  • Pregnancy
  • Receiving renal replacement therapy
  • Glomerular filtration rate less than 10 mL/min
  • Receiving piperacillin/tazobactam or having received piperacillin/tazobactam in the past 7 days before enrolment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03309657


Contacts
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Contact: Jason A Roberts, PhD BPharm +61 7 36468897 j.roberts2@uq.edu.au

Sponsors and Collaborators
Royal Brisbane and Women's Hospital
The University of Queensland
Investigators
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Principal Investigator: Jason A Roberts, PhD BPharm Royal Brisbane and Womens Hospital
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Responsible Party: Royal Brisbane and Women's Hospital
ClinicalTrials.gov Identifier: NCT03309657    
Other Study ID Numbers: HREC/17/QRBW/117
First Posted: October 13, 2017    Key Record Dates
Last Update Posted: October 13, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan to make individual participant data available to other researchers

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Tazobactam
Ceftolozane
Ceftolozane, tazobactam drug combination
Anti-Bacterial Agents
Anti-Infective Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Urinary
Renal Agents