PharmacokineticsPhase 1/2NCT03309657
Pharmacokinetics of Ceftolozane/Tazobactam in Plasma and Cerebrospinal Fluid
A Phase 1/2 study testing Ceftolozane/tazobactam in people with Pharmacokinetics, run by Royal Brisbane and Women's Hospital at 1 site in Australia.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pharmacokinetics
- What is being tested?
- Ceftolozane/tazobactam
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteAustralia
- Study dates
- 1 Feb 2018to 1 Jun 2020
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Australia1 site
Royal Brisbane and Women's Hospital
Brisbane, Queensland, 4029
About this study
Official title: A Prospective Pharmacokinetic Evaluation of the Plasma and Cerebrospinal Fluid Concentrations of a Single Dose Ceftolozane/Tazobactam in Infected Critically Ill Patients With an Indwelling External Ventricular Drain
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.
Read the 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.
- Conditions
- Pharmacokinetics
- Being tested
- Ceftolozane/tazobactam
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ceftolozane/tazobactamDrug
Also called ZERBAXA
This is an observational pharmacokinetic study whereby patients received a single dose of ceftolozane/tazobactam and plasma and cerebrospinal fluid samples were subsequently collected and analyzed to described the pharmacokinetics.
| Study group | Role | What they receive |
|---|---|---|
| Ceftolozane Tazobactam | Experimental | 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. Receives: Drug: Ceftolozane/tazobactam |
What is being measured
The primary outcome is the main question the study is designed to answer.
Unbound Ceftolozane Exposure in the Plasma
Unbound Ceftolozane Exposure in the plasma given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).
Measured: Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis
Unbound Tazobactam Exposure in the Plasma
Unbound Tazobactam Exposure in the plasma given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).
Measured: Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis
Unbound Ceftolozane Exposure in the CSF
Unbound Ceftolozane Exposure in the CSF given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).
Measured: Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis
Unbound Tazobactam Exposure in the CSF
Unbound Tazobactam Exposure in the CSF given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).
Measured: Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Oct 2017
- Study start1 Feb 2018
- Primary completion1 May 2020
- Study completion1 Jun 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for PharmacokineticsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- 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)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Royal Brisbane and Women's Hospital
- Sponsor type
- Other government
- Collaborators
- The University of Queensland
- Responsible party
- Principal investigator, Jason Roberts, Royal Brisbane and Women's Hospital
- Investigators
- Jason A Roberts, PhD BPharm, Principal investigator, Royal Brisbane and Womens Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03309657
- Sponsor's protocol ID
- HREC/17/QRBW/117
- Status last verified
- Aug 2020
- First submitted
- 30 Jul 2017
- Last updated
- 10 Sep 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: There is no plan to make individual participant data available to other researchers
Study at a glance
From the registry record, last updated by the sponsor on 10 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Prospective Pharmacokinetic Evaluation of the Plasma and Cerebrospinal Fluid Concentrations of a Single Dose Ceftolozane/Tazobactam in Infected Critically Ill Patients With an Indwelling External Ventricular Drain
- ClinicalTrials.gov ID
- NCT03309657
- Acronym / sponsor ID
- HREC/17/QRBW/117
- Conditions
- Pharmacokinetics
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Royal Brisbane and Women's HospitalOther government
- Collaborators
- The University of Queensland
- Study start
- 1 Feb 2018 (actual)
- Primary completion
- 1 May 2020 (actual)
- Study completion
- 1 Jun 2020 (actual)
- First posted
- 13 Oct 2017 (actual)
- Results
- Posted 10 Sep 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- 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).
| Arm | Type | Receives |
|---|---|---|
| Ceftolozane Tazobactam | Experimental | Drug: Ceftolozane/tazobactamInfected 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ceftolozane/tazobactamAlso: ZERBAXAThis is an observational pharmacokinetic study whereby patients received a single dose of ceftolozane/tazobactam and plasma and cerebrospinal fluid samples were subsequently collected and analyzed to described the pharmacokinetics. | Drug | Ceftolozane Tazobactam |
Primary outcome
Unbound Ceftolozane Exposure in the Plasma
Time frame: Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis
Unbound Ceftolozane Exposure in the plasma given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).
Unbound Tazobactam Exposure in the Plasma
Time frame: Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis
Unbound Tazobactam Exposure in the plasma given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).
Unbound Ceftolozane Exposure in the CSF
Time frame: Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis
Unbound Ceftolozane Exposure in the CSF given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).
Unbound Tazobactam Exposure in the CSF
Time frame: Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis
Unbound Tazobactam Exposure in the CSF given by the area under the unbound concentration-time curve from time zero to infinity (AUC0-inf).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Sep 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No. There is no plan to make individual participant data available to other researchers
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jason A Roberts, PhD BPharm principal investigator
Royal Brisbane and Womens Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Ceftolozane/tazobactam in people with Pharmacokinetics, run by Royal Brisbane and Women's Hospital at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Unbound Ceftolozane Exposure in the Plasma (time frame: Samples collected from 0 to 8 hours post dose at "0, 1, 2,4,6, & 8 h post dose were use estimate area under the curve from time zero to infinity estimated by non-compartmental analysis). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Sep 2020.