Conditions: Pharmacokinetics
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

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.

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.

Arms:
arm 1: 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.

Interventions: intervention 1: Ceftolozane/tazobactam
Intervention descriptions: intervention 1: 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.

Protocol document:
Prot_SAP_000.pdf: 
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  
Version 2.0 
21/03/2017 
Burns Trauma and Critical Care Research Centre, 
The University of Queensland, Australia 
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 
CLINICAL STUDY PROTOCOL 
PROTOCOL VERSION: 2.0 
PROTOCOL DATE: March 2017 
NCT03309657


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  
 
Version 2.0 
 
21/03/2017 
TABLE OF CONTENTS 
  
TABLE OF CONTENTS .......................................................................................................................... 2	  
LIST OF ABBREVIATIONS ................................................................................................................... 3	  
1. GENERAL INFORMATION ............................................................................................................... 4	  
1.1	   Title ................................................................................................................................................ 4	  
1.2	   Data management centre ............................................................................................................... 4	  
1.3	   Investigators .................................................................................................................................. 4	  
2.  BACKGROUND INFORMATION .................................................................................................... 5	  
2.1 Rationale for the study .................................................................................................................... 5	  
2.2 Study feasibility .............................................................................................................................. 6	  
3. STUDY OBJECTIVE & HYPOTHESIS ............................................................................................. 6	  
3.1 Objective ......................................................................................................................................... 6	  
3.2 Hypothesis....................................................................................................................................... 6	  
4. STUDY DESIGN.................................................................................................................................. 6	  
4.1 The Study ........................................................................................................................................ 6	  
5. ASSESSMENT OF ENDPOINTS ........................................................................................................ 6	  
5.1. Primary endpoints .......................................................................................................................... 6	  
6. SELECTION OF PARTICIPANTS ..................................................................................................... 6	  
6.1 Inclusion criteria ............................................................................................................................. 6	  
6.2 Exclusion criteria ............................................................................................................................ 7	  
7. ASSESSMENT OF PARTICIPANTS .................................................................................................. 7	  
7.1 Study Procedures ............................................................................................................................ 7	  
8. DURATION OF PARTICIPATION .................................................................................................. 11 
9. STUDY TERMINATION .................................................................................................................. 11	  
10. ASSESSMENT OF SAFETY ........................................................................................................... 12	  
10.1 Study Safety Reporting ............................................................................................................... 12 
10.2 Safety Monitoring of Study Participants ..................................................................................... 12 
10.3 Management of Safety Risks ...................................................................................................... 13 
11. ETHICAL CONSIDERATIONS ...................................................................................................... 13	  
11.1 Ethical Principles ........................................................................................................................ 13	  
11.2 Confidentiality and Privacy ........................................................................................................ 14 
11.3 Participant Consent ..................................................................................................................... 14	  
12. FINANCING AND INSURANCE ................................................................................................... 15	  
12.1 Funding and Indemnity ............................................................................................................... 15	  
13. PROJECT TIMELINE ...................................................................................................................... 15	  
14. REFERENCES ................................................................................................................................. 15 
15. APPENDICES .................................................................................................................................. 15 
 
 


A prospective pharmacokinetic evaluation of the plasma and cerebrospinal fluid concentrations of a 
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LIST OF ABBREVIATIONS 
 
AIC 
 
 
Akaike Information Criterion 
 
BBB 
 
 
Blood-brain-barrier 
 
BIC 
 
 
Bayesian Information Criterion 
 
BTCCRC 
 
Burns Trauma and Critical Care Research Centre 
 
CRF 
 
 
Case report form 
 
CSF 
 
 
Cerebrospinal fluid 
 
EVD 
 
 
External ventricular drain 
 
HPLC 
 
 
High performance liquid chromatography 
 
HREC  
 
Human Research Ethics Committee 
 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
 
ICU 
 
 
Intensive care unit 
 
LC-MS  
 
Liquid chromatography–mass spectrometry 
 
LOQ 
 
 
Limit of quantification 
 
MDR 
 
 
Multi-drug-resistant 
 
MIC 
 
 
Minimum inhibitory concentration 
 
MS 
 
 
Mass spectrometry 
 
MSC 
 
 
Management Systems Certification 
 
PD 
 
 
Pharmacodynamic 
 
 
 
PK 
 
 
Pharmacokinetic 
 
PK/PD  
 
Pharmacokinetic/pharmacodynamic 
 
RBWH  
 
Royal Brisbane and Women’s Hospital 
 
SAE 
 
 
Serious Adverse Event 
 
SDM 
 
 
Substitute decision maker 
 
SOFA 
 
 
Sepsis-related Organ Failure Assessment 
 
SPC 
 
 
Summary of Product Characteristics 
 
SUSAR  
 
Suspected Unexpected Serious Adverse Reaction 
 
UQCCR  
 
The University of Queensland Centre for Clinical Research 
 


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  
 
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1. GENERAL INFORMATION 
 
1.1   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   
 
 
 
 
 
 
 
Chief Investigator 
 
 
Name:  
 
Professor Jason Roberts 
 
Title: 
Professor of Medicine and Pharmacy 
 
 
Burns Trauma and Critical Care Research Centre,  
 
 
UQCCR and School of Pharmacy 
 
 
The University of Queensland 
 
 
 
Address: 
Level 8, UQCCR  
 
 
 
 
Building 71/918, Royal Brisbane and Women’s Hospital 
 
 
 
 
Herston, Brisbane QLD 4029 
 
Contact Number:  
+ 61 409 769 397   
 
Email:  
 
j.roberts2@uq.edu.au  
 
1.2  
Data management centre 
 
 
Name: 
Burns Trauma and Critical Care Research Centre,  
 
 
The University of Queensland  
 
 
Level 8, UQCCR  
 
 
Building 71/918, Royal Brisbane and Women’s Hospital 
 
 
Herston, Brisbane QLD 4029 
 
 
 
 
Australia 
 
1.3  
Investigators: 
The University of Queensland – Dr Steven Wallis, Professor Jeffrey Lipman, Dr Menino Osbert Cotta 
Royal Brisbane and Women’s Hospital – Ms Janine Stuart 


A prospective pharmacokinetic evaluation of the plasma and cerebrospinal fluid concentrations of a 
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2.  BACKGROUND INFORMATION 
2.1 Rationale for the study 
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 [1]. 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) [1, 2]. 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 [2]. 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 treatment 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 [3]. 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 [3-5]. 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 3g 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. intra-ventricular 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. 
 
 
 


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  
 
Version 2.0 
 
21/03/2017 
2.2 Study feasibility 
The intensive care unit (ICU) at the Royal Brisbane and Women’s Hospital (RBWH) is a 30-bed 
tertiary-level ICU that serves as a major referral centre for neurosurgical patients. A significant 
proportion of these neurosurgical patients have EVDs in situ as part of their routine clinical care in the 
ICU. As such, the prospective pharmacokinetic (PK) study describing both the plasma and CSF PK of 
a single dose of ceftolozane/tazobactam in ten critically ill patients with indwelling EVD aged ≥ 18 
years is highly feasible. The Burns, Trauma and Critical Care Research Centre (BTCCRC), UQCCR, 
The University of Queensland, which has extensive experience in antibiotic PK studies and is affiliated 
with RBWH, will oversee the overall project management. 
 
3. STUDY OBJECTIVE & HYPOTHESIS 
3.1 Objective 
The objective of the study is to describe the pharmacokinetics of a single dose of 
ceftolozane/tazobactam in the plasma and CSF in critically ill patients with an indwelling EVD. 
 
3.2 Hypothesis 
1.   The plasma PK of cefolozane/tazobactam may be altered in critically ill patients with an 
indwelling EVD. 
2.   The distribution of ceftolozane/tazobactam into the CSF may be impaired by the BBB. 
 
4. STUDY DESIGN 
4.1 The Study 
This is an open-label, single-dose PK study that will describe both the plasma and CSF PK of a single 
dose of ceftolozane/tazobactam in ten critically ill patients with indwelling EVD aged ≥ 18 years. 
 
5. ASSESSMENT OF ENDPOINTS  
5.1. Primary endpoints 
The primary endpoint will be the development of a population PK model as well as dosing simulations 
that 
are 
likely 
to 
achieve 
pharmacokinetic/pharmacodynamic 
(PK/PD) 
targets 
of 
ceftolozane/tazobactam based on presumed or confirmed etiologic bacterial pathogens. 
 
6. SELECTION OF PARTICIPANTS 
6.1 Inclusion criteria  
Patients treated in the ICU are eligible for inclusion in the study if ALL of the following criteria are 
met: 
•  
Age ≥ 18 years  


A prospective pharmacokinetic evaluation of the plasma and cerebrospinal fluid concentrations of a 
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•  
The presence of an indwelling external ventricular drain (EVD) or requiring EVD insertion 
due to obstructive hydrocephalus/subarachnoid haemorrhage 
6.2 Exclusion criteria  
Patients are excluded from the study if ONE OR MORE of the following criteria are met: 
•  
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 
 
7. ASSESSMENT OF PARTICIPANTS 
7.1 Study Procedures 
Study Protocol (Figure 1) 
Patient enrolment: 
All patients admitted to the ICU at RBWH during the study period will be screened for eligibility to 
participate in this study based on the under listed inclusion and exclusion criteria. Clinical staff in the 
ICU will identify potential patients that may be suitable for inclusion into the study. The clinical 
research team will further assess patients suitable for participation. As patients will not be in a position 
to give consent due to medical sedation or unconsciousness or severe illness, the patient’s authorised 
representative (termed ‘substitute decision maker’) will be approached for informed consent. 
Investigators will explain the procedures of the study verbally in addition to the structured Person 
Responsible Information Sheet and Consent Form that will be provided to the substitute decision maker 
(SDM) prior to consenting. Following their enrolment and participation in the study, a Participant 
Information Sheet and Consent Form will be provided to the patient, seeking their consent for 
continued participation in the study. A total of ten patients will be enrolled. 
 
Enrolment Log: 
An enrolment log will be used to record patient recruitment to the study. This will be maintained by the 
research staff. 
 
Study drug: 
Ceftolozane sulfate/tazobactam sodium (Zerbaxa) is a white to yellow powder for solution. Each vial 
contains 1000 mg of ceftolozane (as ceftolozane sulfate) and 500mg tazobactam (as tazobactam 
sodium). Each vial contains the following inactive ingredients: sodium chloride, arginine and 
anhydrous citric acid. 
 


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Merck Sharp and Dohme (Australia) Pty Limited shall make available sufficient quantities of Study 
drug free of charge to carry out the study. The sponsor (University of Queensland) and the Chief 
Investigator shall be responsible for the maintenance of appropriate records and assure appropriate 
supply, handling, storage, distribution and usage of the Study Drug in accordance with the Protocol. 
The supplied Study Drug will not be used for any other purpose other than stated in the protocol. There 
will be no cost to the study participants. 
 
Drug administration:  
Each vial of ceftolozane/tazobactam will be reconstituted with 10 mL of sterile water for injection or 
0.9% Sodium Chloride for injection (normal saline) and gently shaken to dissolve. For preparation of 
the specified dose: the entire contents of each reconstituted vial will be withdrawn and added to an 
infusion bag containing 100 mL of 0.9% Sodium Chloride for Injection (normal saline) or 5% Glucose 
Injection. The study participants will receive a single dose of 3g ceftolozane/tazobactam (2g 
ceftolozane + 1g tazobactam, i.e. two vials) via intravenous infusion over 1 hour. 
Ceftolozane/tazobactam is to be infused through a dedicated peripheral line, or through a dedicated 
lumen of a central venous catheter or peripherally inserted central catheter line. No other medications 
or fluids are to be infused through the lumen dedicated to study drug during study drug administration. 
The line will be flushed at the conclusion of the infusion. The dose will be administered while the EVD 
is in place. 
 
Sample collection:  
Blood sample collection 
Arterial blood samples (2 to 3 mL for each sample) will be collected on 12 occasions (i.e. prior to dose 
administration, and serially at 15 min, 45 min, 75 min (after 15 min line flushing), 2 hours, 3 hours, 4 
hours, 5 hours, 6 hours, 7 hours, 8 hours, 24 hours).  
 
CSF sample collection 
CSF samples (0.5 to 1 mL) will be simultaneously collected from the EVD on 6 occasions (prior to 
dose administration, at 2 hours, 4 hours, 6 hours, 8 hours, 24 hours). The drip chamber of the EVD 
system will be emptied about 30 minutes before the first CSF sample collection and after each sample 
collection. In addition, the entire volume of the CSF drainage during the eight hours of sampling will 
be recorded and collected. The actual time of collection for individual samples will be recorded and 
used in the analysis. All samples will be coded and stored in the ICU Research Laboratory and will be 
analysed at the BTCCRC laboratory located on the RBWH campus. Sample handling procedures as per 
Attachments - Appendix A. 
 
Urine sample collection 


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Total volume of urine produced over the 24-hour sampling period will be collected. A 1mL aliquot will 
be kept to analyse the amount of drug cleared into urine over the dosing interval and the rest will be 
used to measure the patient’s urinary creatinine clearance. 
 
 
Clinical Data Collection:  
A structured data collection sheet will be used to collect patient specific clinical data exclusively from 
electronic and paper based patient medical records, including: 
•  
Admission details 
•  
Demographic data - initials, date of birth, gender, race, medical history, height, weight 
•  
Physical examination including vital signs 
•  
Acute Physiology and Chronic Health Evaluation II [APACHE II] and APACHE III score and 
risk of death at ICU admission 
•  
Sequential Organ Failure Assessment [SOFA] score at ICU admission 
•  
Presence of shock on day of sampling 
•  
Presence of mechanical ventilation on day of sampling 
•  
Concurrent medications on day of sampling 
•  
Diagnosis/es 
•  
Patient co-morbidities 
•  
Clinical hematological and biochemical data on day of sampling including: total white cell 
count, neutrophil count, platelet count, serum creatine concentration, hepatic function markers 
(alanine aminotransferase [ALT], aspartate aminotransferase [AST], alanine phosphatase 
[ALP], gamma glutamyl transferase [GGT], international normalised ratio [INR], bilirubin). 
  
All case report forms and other data (including, without limitation, written, printed, graphic, video and 
audio material, and information contained in any computer database or computer readable form) 
created or developed in connection with the Study will be owned by the Chief Investigator. All data 
will be collected by study research staff.  
 
Sample assay:  
After sampling, all samples will be stored at -80oC until assayed.  The concentrations of ceftolozane 
and tazobactam in the biological samples will be determined by chromatographic methods (HPLC and 
LC-MS/MS) that are validated and conducted in accordance with the Food and Drug Administration’s 
guidance for industry on bioanalysis. The limit of quantification (LOQ) of the assay methods will be 
<0.1 mg/L for both ceftolozane and tazobactam. The validated concentrations will be submitted for 
population pharmacokinetic analysis and dosing simulation with PK/PD analysis. 
 
Population Pharmacokinetic Analysis:  


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NONMEM software (version 7.3, GloboMax LLC, Hanover, MD) will be used for population PK 
analysis. A stepwise approach will be following in the model building process: (i) determination of the 
structural base model; (ii) selection of the best fit statistical error model (iii) development of covariate 
model, (iv) and finally model evaluation.  
(i) Determination of the structural base model: Different structural models based on one, two or 
three compartment will be fitted to the concentration-time data using NONMEM subroutines. Both 
linear and/or Michaelis–Menten kinetics will be assessed for elimination and distribution of the drug. 
Also linear and/or non-linear binding to plasma proteins will be considered.  
ii) Selection of the best fit statistical error model: Inter-individual variability will be assumed to 
follow a log-normal distribution. For the residual error model additive, proportional and a combination 
of additive and proportional models will be tested.   
(iii) Development of covariate model: Available clinical covariates will be assessed for biological 
plausibility and subsequently evaluated in the covariate analysis. Selected covariates will be tested on 
the structural model parameters (volume(s) of distribution and clearance). Standard covariate 
evaluation algorithms will be followed through forward addition and backward elimination or a 
combination of forward addition and backward elimination in a stepwise fashion.  
(iv) Model evaluation: Diagnostic plots and statistical examination through objective function values 
will be used for comparison of models. Diagnostic plots will include scatter plot of residuals versus 
predicted values, scatter plot of observed values versus predicted values and scatter plot of weighted 
residuals versus explanatory variables. Objective functions will include log-likelihood ratio test for 
nested model. A decrease in objective function value by greater than 3.84 (which corresponds to p < 
0.05 based on chi-square test) will be considered statistically significant. Other objective function 
values also, Akaike Information Criterion (AIC) or Bayesian Information Criterion (BIC) will be 
examined. Finally, the stability of the final model will be assessed by the nonparametric bootstrapping 
method.  
 
Dosing Simulations with PK/PD analysis: Subsequent to population PK analysis, Monte Carlo 
simulations for drug concentrations in plasma will be performed using reported minimum inhibitory 
concentrations (MICs) of the presumed or confirmed etiologic bacterial organisms, or specific bacterial 
MICs if determined. 
 
 
 
 
 
 
 
 
 


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Figure 1: Study protocol 
 
 
8. DURATION OF PARTICIPATION 
The duration of study for each patient will be 24 hours following administration of a single dose of 
ceftolozane/tazobactam. 
 
9. STUDY TERMINATION 
The study may be terminated at any time at the request the Chief Investigator, or a regulatory authority, 
with proper and timely notification of all parties concerned. The Independent Ethics Committee will be 
informed promptly and the investigator will supply reason(s) for the termination or suspension, as 


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specified by the applicable regulatory requirements. Otherwise, the study is considered terminated 
upon completion of all patient treatments and evaluations. 
 
10. ASSESSMENT OF SAFETY 
10.1 Study Safety Reporting 
10.1.1 Serious Adverse Event 
All patients will be monitored for potential development of Serious Adverse Events (SAEs) which are 
defined as any untoward medical occurrence that meets one or more of the following criteria: 
• Results in death; 
• Is life-threatening; 
• Requires inpatient hospitalisation or prolongation of existing hospitalisation; 
• Results in persistent or significant disability/incapacity; 
• Is a congenital anomaly/birth defect; or 
• Is an important medical event which may require intervention to prevent one of the previously 
listed outcomes? 
 
10.1.2 Suspected Unexpected Serious Adverse Reaction 
Suspected Unexpected Serious Adverse Reaction (SUSAR) is any SAE, the nature, severity or 
frequency of which is not consistent with information in the most current Summary of Product 
Characteristics (SPC) or Package insert. Any adverse event, SAE or SUSAR will be recorded in the 
study CRF and managed in the ICU in line with best clinical practice according to the patient 
symptoms. 
 
10.2 Safety Monitoring of Study Participants 
Monitoring the safety of study participant and the progress of the study will be made at two levels. 
Firstly, the ICU research management forum at the study site, which is attended by all intensive care 
specialists, will be used for a comprehensive appraisal of the study protocol including assessment of 
risk to study participants. Monthly meetings of this forum will be used to evaluate the progress of the 
conduct of the study based on first-hand experience during the conduct of the study.  
 
Secondly, on a day to day basis participants will be monitored for potential SAEs and SUSARs. This 
monitoring will be done by nursing staff, doctors treating the patient and the research team. The 
clinical staff at the study site (nurses and doctors) will be aware when a patient is enrolled in the study 
and will be requested to remain vigilant for any ADRs or SUSARs. Nurses look after the patients in the 
ICU 24 hours per day (one nurse for one patient) and this provides a constant monitoring of the 
patients. In addition doctors will examine the patient multiple times per day. Further to these, the 
clinical pharmacists and research team will provide additional reviews of the patient. Following these 
reviews, investigators of the study will report any ADRs or SUSARs related to the study drug both to 


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the RBWH Human Research Ethics Committee (HREC) and the sponsors. The SAE reports will be 
forwarded to the HREC in accordance with local requirements. The Chief Investigator of the study is a 
consultant pharmacist and has the required expertise to assist and advice the HREC about reports of 
serious adverse events. 
 
The Chief Investigator will forward to MSC Global Safety Group (fax number: +1-215-993-1220) any 
SAE and SUSAR information within 2 business days of learning of the information. The SAE reports 
will be forwarded to the Independent Ethics Committee in accordance with local requirements. 
 
The Chief Investigator agrees to perform the study in accordance with this study protocol, the 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and the applicable regulatory requirements. The Chief 
Investigator is required to ensure compliance with all procedures required by the study protocol. 
 
10.3 Management of Safety Risks 
There are risks to participants involved with the conduction of this study: mainly an increased risk of 
developing or worsening CNS infection related to CSF sampling via the EVD. Patients undergo routine 
CSF sampling once per day as part of standard care and survelliance. For this study, the EVD will be 
accessed 6 times, however, investigators will incorporate routine sampling into the study to reduce 
sampling times over the 24 hour period. So in effect, the EVD will be accessed an additional 4 times. 
Two samples will be divided into two aliquots with one going to the local laboratory for routine 
evaluation and the other aliquot being used for the study analysis. This increased risk will be minimised 
by strict adherence to RBWH ICU guidelines/protocol for safe and effective CSF sampling from an 
EVD. The person sampling CSF from the EVD will be a research nurse specially trained as per these 
guidelines/protocol. Although there is added risk associated with more frequent CSF sampling via the 
EVD, this is justified given that more frequent sampling will greatly improve the accuracy in 
describing the exposure of ceftolozane/tazobactam in the CSF. 
 
 
11. ETHICAL CONSIDERATIONS 
11.1 Ethical Principles 
This study is to be performed in accordance with the ethical principles of the Declaration of Helsinki 
and all relevant national and local guidelines on the ethical conduct of research. Prior to 
commencement, the study protocol will be presented to the HREC at the RBWH for approval. Local 
governance approval will then be sought. The Chief Investigator will be responsible for submitting 
progress reports, adverse event reports and any other required documentation to the HREC in 
accordance with their guidelines. Copies of all HREC and research governance correspondence will be 
kept with the study investigator files. 


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11.2 Confidentiality and Privacy 
Patients enrolled will be allocated a unique study number. The Research Coordinator will compile an 
enrolment log including the patient’s name, date of birth, hospital identification number, unique study 
number and date and time of enrolment. Subsequent data will be identified by the unique study number 
only. The enrolment log and study data will be kept separately. All patient details and study data will 
be kept in a locked office at the study site. No identifying data will be entered into the electronic data 
base. 
 
All study data will be entered into a secure computer maintaining confidentiality in accordance with 
local legislation on privacy and use of health data. When archiving or processing data pertaining to the 
investigator/and or patients, the coordinating centre will take all appropriate measures to safeguard and 
prevent access to this data by any unauthorised party. 
 
The Chief Investigator will maintain the confidentiality of all study documentation, and take measures 
to prevent accidental or premature destruction of these documents. The Chief Investigator will retain 
the study documents at least fifteen years after the completion or discontinuation of the study. The 
Chief Investigator will be notified prior to the destruction of any study essential documents following 
the study completion or discontinuation. If the Chief Investigator's personal situation is such that 
archiving can no longer be ensured by him/her, the investigator shall inform the sponsor,  MSD and the 
local HREC of these changes in circumstances and the relevant records shall be transferred to a 
mutually agreed designee. 
  
11.3 Participant Consent 
The Chief Investigator or their nominated delegate will obtain written informed consent from any 
conscious and comprehending patient, prior to enrolment in the study. Obtaining written and informed 
consent directly from patients in the ICU prior to enrolment in the study will not be possible because 
these patients are often unconscious, sedated, intubated and too ill to understand information relating to 
study participation. Under these circumstances, the approach to obtaining consent in this study will be 
based on the guidelines of the Australian National Health and Medical Research Council (NHMRC) 
National Statement (i.e. consent will be obtained from their SDM). The procedure for obtaining 
consent from the patient’s SDM will be approved by the local HREC prior to use. SDMs will be given 
a verbal explanation of the study and the Person Responsible Information Sheet and Consent Form to 
read. They will be given opportunity to ask questions prior to deciding on participation of the 
participant. If the SDM consents to the participant’s participation in the study they will be given a copy 
of the signed Person Responsible Information Sheet and Consent Form. Following their enrolment and 
participation in the study, a Participant Information Sheet and Consent Form will also be provided to 
the participant, seeking their consent to continued participation in the study. If the partipant consents to 


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their continued participation in the study, they will be given a copy of the signed Participant 
Information Sheet and Consent Form. 
 
All interaction between research staff and potential or actual participants and their SDMs will take into 
consideration the stress or emotional factors associated with critical illness and ensure that the 
dependency of potential participants and their SDMs on medical personnel providing treatment does 
not compromise the freedom of decision making to participate. 
 
12. FINANCING AND INSURANCE  
12.1 Funding and Indemnity 
All costs related to ethics preparation, patient enrolment, data collection and sample collection assaying 
will be incurred by The University of Queensland. 
 
MSD has provided The University of Queensland (Sponsor) with funding in support of this study. The 
University of Queensland will contract with the Intensive Care Services Research Office at the Royal 
Brisbane and Women’s Hospital to conduct the study within the ICU. These payments are for services 
provided by the Chief Investigator and third party entities i.e. research staff at Royal Brisbane and 
Women’s Hospital. Indemnity will be provided by the University of Queensland and Metro North 
Hospital Health Services District. 
 
13. PROJECT TIMELINE 
Date 
Project Milestone 
February 2017 
CRF and Patient information and consent documents 
March 2017 
Ethics application to Independent Ethics Committee  
April 2017 to February 2019 
Patient recruitment 
March to April 2019 
Database lock, data analysis and initial results 
 
14. REFERENCES 
1. 
Meningitis - Gram-negative [https://www.nlm.nih.gov/medlineplus/ency/article/000610.htm] 
2. 
O'Neill E, Humphreys H, Phillips J, Smyth EG: Third-generation cephalosporin resistance 
among Gram-negative bacilli causing meningitis in neurosurgical patients: significant challenges in 
ensuring effective antibiotic therapy. The Journal of antimicrobial chemotherapy 2006, 57(2):356-359. 
3. 
Sader HS, Farrell DJ, Castanheira M, Flamm RK, Jones RN: Antimicrobial activity of 
ceftolozane/tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various 
resistance patterns isolated in European hospitals (2011-12). The Journal of antimicrobial 
chemotherapy 2014, 69(10):2713-2722. 


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single dose ceftolozane/tazobactam in infected critically ill patients with an indwelling external 
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4. 
Bulik CC, Christensen H, Nicolau DP: In vitro potency of CXA-101, a novel cephalosporin, 
against Pseudomonas aeruginosa displaying various resistance phenotypes, including multidrug 
resistance. Antimicrob Agents Ch 2010, 54(1):557-559. 
5. 
Sader HS, Rhomberg PR, Farrell DJ, Jones RN: Antimicrobial activity of CXA-101, a novel 
cephalosporin tested in combination with tazobactam against Enterobacteriaceae, Pseudomonas 
aeruginosa, and Bacteroides fragilis strains having various resistance phenotypes. Antimicrob Agents 
Ch 2011, 55(5):2390-2394. 
 
15. APPENDICES 
Appendix A: Sample Collection, Handling and Storage 
 
Plasma Samples 
•  
Blood (1 to 2 mL) will be collected into a 3 ml Lithium Heparin tube, with or without 
separator gel (acceptable alternate anticoagulants to be announced). 
•  
Blood samples should be kept chilled on ice or in the fridge until centrifugation (within 6 
hours). 
•  
Blood samples should be centrifuged at 3000 rpm for 10 minutes to separate plasma. 
•  
Plasma (approximately 1 mL) should be transferred into a labelled cryovial and stored at -
80°C until analysis. 
CSF samples 
CSF will be collected in lithium heparin tubes and centrifuged (3000 rpm for 10 minutes) to separate 
out any red cells that may be present. The samples will be aliquoted and frozen at ¯80°C until 
recruitment is complete. 
•  
CSF (0.5 to 1 mL) will be transferred to a labelled cryovial prior after sampling via the EVD. 
•  
CSF samples will then be chilled on ice or in the fridge until stored at -80°C prior to analysis.