A Phase 1, Non-comparative, Open-label Study to Characterize the Pharmacokinetics of a Single Intravenous Dose of Ceftolozane/Tazobactam in Pediatric Patients Receiving Standard of Care Antibiotic Therapy for Proven or Suspected Gram-negative Infection or for Peri-operative Prophylaxis
Phase: PHASE1
Conditions: Proven or Suspected Gram-negative Bacterial Infection, Peri-operative Prophylaxis
Sponsor: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Phase 1, Non-comparative, Open-label Study to Characterize the 
Pharmacokinetics 
of 
a 
Single 
Intravenous 
Dose 
of 
Ceftolozane/tazobactam in Pediatric Patients Receiving Standard of 
Care Antibiotic Therapy for Proven or Suspected Gram-negative 
Infection or for Peri-operative Prophylaxis 
NCT number: 
NCT02266706 
Document Date: 
09-Feb-2017 

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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
CEFTOLOZANE/TAZOBACTAM
CXA-PEDS-13-08
A PHASE 1, NON-COMPARATIVE, OPEN-LABEL STUDY TO CHARACTERIZE 
THE PHARMACOKINETICS OF A SINGLE INTRAVENOUS DOSE OF 
CEFTOLOZANE/TAZOBACTAM IN PEDIATRIC PATIENTS RECEIVING 
STANDARD OF CARE ANTIBIOTIC THERAPY FOR PROVEN OR SUSPECTED 
GRAM-NEGATIVE INFECTION OR FOR PERI-OPERATIVE PROPHYLAXIS
Study Drug:
ceftolozane/tazobactam
IND Number:
104,490
Protocol Number:
CXA-PEDS-13-08 (MK-7625A PN010)
Sponsor:
Cubist Pharmaceuticals LLC (formerly known as 
Cubist Pharmaceuticals, Inc.), an indirect wholly-
owned subsidiary of Merck & Co., Inc. and with a 
principal place of business address of:
Weystrasse 20 - 6000 Lucerne 6
Switzerland
Dose Form:
Intravenous
Medical Monitor:
Version:
5.0
Amendment:
4.0
Date:
09 February 2017
STATEMENT OF CONFIDENTIALITY
The confidential information in the following document is provided to you as an investigator, 
potential investigator, or consultant, for review by you, your staff, and applicable institutional 
review board(s).  It is understood that the information will not be disclosed to others without 
written authorization from Cubist Pharmaceuticals, LLC, except to the extent necessary to 
obtain informed consent from those persons to whom the drug may be administered.
PPD

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PROTOCOL Approval
Protocol Title:
A Phase 1, Non-comparative, Open-label Study to 
Characterize the Pharmacokinetics of a Single 
Intravenous Dose of Ceftolozane/tazobactam in 
Pediatric Patients Receiving Standard of Care Antibiotic 
Therapy for Proven or Suspected Gram-negative 
Infection or for Peri-operative Prophylaxis
Protocol Number:
CXA-PEDS-13-08
Protocol Date:
09 February 2017
Date
 
 
Date
Date
PPD
PPD
PPD
PPD
PPD
PPD

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Investigator’s Agreement
I have received and read the Investigator’s Brochure for ceftolozane/tazobactam. I have read 
the CXA-PEDS-13-08 protocol and agree to conduct the study as outlined.  I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.
Printed Name of Investigator
Signature of Investigator
Date

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SUMMARY OF CHANGES
PRIMARY REASONS FOR THIS AMENDMENT:
Section 
Numbers
Section Titles
Description of Changes
Rationale
Synopsis, 
1.4.1, 
3.1, 
4.1
Synopsis
Study Rationale
Overall Study Design
Subject Inclusion 
Criteria
For Group 6 only, Inclusion Criterion 6 was 
expanded from peri-operative prophylaxis 
only to any antibiotic prophylaxis.
For Group 6 subjects born at ≤32 weeks 
gestation who are <3 months of age, surgery 
is commonly delayed due to immaturity and 
their small size. These subjects may still be 
receiving antibiotic prophylaxis and be 
appropriate candidates for the study despite 
not being in a peri-operative period.
Synopsis, 
4.2
Synopsis, 
Subject 
Exclusion 
Criteria
For Group 6 only, height and weight criteria 
were removed from Exclusion Criterion 6.
For Group 6 subjects born at ≤32 weeks 
gestation who are <3 months of age, there are 
no validated or standardized tools to assess 
percentiles for height or weight. In addition, 
height is accounted for in the calculation of 
creatinine clearance using the Schwartz 
equation.

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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Numbers
Section Titles
Description of Changes
Rationale
Title Page, 
Protocol 
Approval 
Page
Title Page, 
Protocol Approval Page
Medical Monitor name was changed.
Administrative change.
Throughout 
the 
document
Throughout the 
document
Minor stylistic and typographical edits were 
made.
To align with Merck style, improve clarity, or 
both.

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SYNOPSIS
Name of Sponsor/Company: Cubist Pharmaceuticals, LLC
Name of Investigational Product: ceftolozane/tazobactam
Name of Active Ingredient: ceftolozane/tazobactam
Title of Study: A Phase 1, Non-comparative, Open-label Study to Characterize the 
Pharmacokinetics of a Single Intravenous Dose of Ceftolozane/tazobactam in Pediatric Patients 
Receiving Standard of Care Antibiotic Therapy for Proven or Suspected Gram-negative Infection or 
for Peri-operative Prophylaxis
Phase of Development: 1
Objectives: 
Primary:
To evaluate the pharmacokinetics (PK) of a single dose of intravenous ceftolozane/tazobactam in 
pediatric patients from birth to <18 years receiving standard of care antibiotic therapy for proven or 
suspected gram-negative infection, including patients receiving peri-operative prophylactic 
antibiotics.
Secondary:
To assess the safety and tolerability of a single dose of intravenous ceftolozane/tazobactam in 
pediatric patients from birth to <18 years receiving standard of care antibiotic therapy for proven or 
suspected gram-negative infection, including patients receiving peri-operative prophylactic 
antibiotics.
Study Rationale:
Ceftolozane/tazobactam is a novel antibacterial consisting of ceftolozane, a unique antipseudomonal 
cephalosporin, with tazobactam, a well-established β-lactamase inhibitor.  This antibacterial has
activity against Pseudomonas aeruginosa, including drug-resistant strains, and other common 
gram-negative pathogens including extended-spectrum β-lactamase (ESBL)-producing 
Enterobacteriaceae.  Ceftolozane/tazobactam is being developed in adults for the treatment of 
serious gram-negative bacterial infections including complicated urinary tract infections, 
complicated intra-abdominal infections, and nosocomial pneumonia. 
This is the first study investigating the use of ceftolozane/tazobactam in pediatric patients. Current 
guidance documents for pediatric PK studies focus on appropriate dosing in the pediatric population 
based on PK data. The PK of a drug in the pediatric population usually cannot be precisely predicted 
from that in adults. Therefore, PK studies are needed to identify the appropriate pediatric dosing.
In general, the initial pediatric doses of ceftolozane/tazobactam were chosen based on adult PK data, 
with the objective of achieving the therapeutic exposure levels seen in adults. However as, 
ceftolozane/tazobactam is primarily renally eliminated the initial doses for each age group will take 
into account the stage of development of their renal function and body weight.
This study is designed to assess the PK, safety, and tolerability of a single intravenous dose of 
ceftolozane/tazobactam in pediatric patients.

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Methodology: 
This is a Phase 1, single-dose, non-comparative, open-label study to characterize the PK, safety, and 
tolerability of ceftolozane/tazobactam in male and female pediatric patients from birth to <18 years 
receiving concurrent standard of care antibiotic therapy for proven or suspected gram-negative 
infection including patients receiving peri-operative prophylactic antibiotics.
Thirty-six eligible patients will be enrolled into one of six age groups (6 patients planned per age 
group):  

Group 1: Ages ≥12 to <18 years

Group 2: Ages ≥7 to <12 years 

Group 3: Ages ≥2 to <7 years

Group 4: Ages ≥3 months to <2 years

Group 5: Ages birth (>32 weeks gestation, 7 days postnatal) to <3 months 

Group 6: Ages birth (≤32 weeks gestation, 7 days postnatal) to <3 months
In Groups 5 and 6, birth has been defined as at least 7 days postnatal due to the fact that neonatal 
renal function is closely related to both gestational age and postnatal age. Fluctuations in serum 
creatinine occur in the first week of life and as a result, the Schwartz equation, which will be used to 
calculate renal function in this population, is not recommended for use until after the first week of 
life. Because ceftolozane/tazobactam is primarily renally eliminated, it is necessary to limit 
enrollment in Groups 5 and 6 only to those patients who have undergone the fluctuation in serum 
creatinine observed during the first week of life, hence the requirement for 7 days postnatal.  A 
subanalysis of Groups 5 and 6 will be conducted in patients aged 7-28 days and those aged 29 days -
<3 months. 
All patients will receive a single age-based IV dose of ceftolozane tazobactam as a 60 (± 10) minute 
infusion.
In each age group, an interim analysis of PK and safety data will be conducted after 3 patients have 
received the initially proposed dose.  For Groups 5 and 6, an additional interim analysis will be 
conducted after a total of 3 patients across both groups have been dosed. This additional interim 
analysis will only be performed if the first 3 patients span across both groups, and will not be 
required if the first 3 patients are consecutively enrolled into either Group 5 or Group 6.  Depending 
on the results of the interim analysis, dosing will either continue at the initial dose, or a new 
optimized dose targeted at achieving the exposure levels seen in adult patients.
In subsequent groups, the initial dose is also subject to change based upon the results of the interim 
analysis in previous groups. 
Enrollment will begin with Groups 1-4 at study start. Enrollment of Groups 5-6 will occur 
following interim analysis of Group 4, and will be based on preliminary PK assessments, PK 
variability, and patient safety data.  
Screening assessments, including medical and surgical history, medication history, nursing mothers’ 
medication history, demographics, physical examination, vital signs, ECG, urinalysis, and clinical 
laboratory tests (hematology, chemistry, urinalysis, serum creatinine, and direct Coombs’ test) will 
be performed within 48 hours prior to dosing. 
Blood samples for plasma PK determination of ceftolozane, tazobactam, and tazobactam M1 (the 
single major metabolite of tazobactam) plasma levels will be collected in all patients.
Patients will be monitored for safety 24 hours post study-drug infusion, including assessments of 
adverse events (AEs), physical examination, vital signs, and clinical laboratory tests. 

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The site will contact the patient and/or parent (or appropriate legal representative) at Study Day 8 
(± 2 days) for assessment of AEs and concomitant medications and procedures.
Number of Patients (planned): 
Thirty-six patients concurrently receiving standard of care antibiotic therapy for proven or suspected 
gram-negative infection or for peri-operative prophylaxis are planned to be enrolled into one of six 
age groups: ≥12 to <18 years, ≥7 to <12 years, ≥2 to <7 years, ≥3 months to <2 years, birth (>32 
weeks gestation, 7 days postnatal) to <3 months, and birth (≤32 weeks gestation, 7 days postnatal) to 
<3 months.  
Inclusion Criteria: 
To be eligible for enrollment, a patient must fulfill all of the following inclusion criteria:
1.
Provide written parental (or appropriate legal representative) informed consent and age-
appropriate assent prior to any study-related procedure not part of normal medical care;
2.
Male or female from birth (defined as at least 7 days postnatal) to  <18 years of age; 
3.
Able to comply with the protocol for the duration of the study;
4.
For female patients who have undergone menarche:

Is not pregnant (as confirmed by the serum pregnancy test at Screening) and not 
planning to become pregnant within 30 days of last study drug administration, 
AND 

Is non-lactating, AND

Is abstinent OR utilizes one of the following for at least 1 month prior to screening: 
hormonal contraceptives (injectable, oral, patch, or vaginal ring), intrauterine 
device (IUD), or barrier method (diaphragm).  This method must be used in 
combination with a barrier method of contraception for their male partner 
(condom). Patients must be willing to practice these methods for at least 30 days 
after study drug administration; 
5.
For male patients who are sexually active with female partners who have undergone 
menarche: patient must be using and willing to continue using medically acceptable forms 
of contraception (abstinence, or male condom for patients plus an additional method of 
contraception for their female partners) from Screening and for at least 30 days after study 
drug administration;  
6.
For Groups 1-5:

Receiving standard of care antibiotic therapy for suspected or diagnosed gram-
negative infection or for peri-operative prophylaxis
For Group 6:

Receiving standard of care antibiotic therapy for suspected or diagnosed 
gram-negative infection or as antibiotic prophylaxis;
7.
For Groups 1–4: 

Have a calculated creatinine clearance rate (CLCR) ≥ 80 mL/min/1.73m2 as 
determined by the Schwartz (2009) equation at baseline.
For Group 5: 

Have a calculated creatinine clearance rate (CLCR) ≥ 50 mL/min/1.73m2 as 
determined by the Schwartz (2009) equation at baseline.
For Group 6:

Have a calculated creatinine clearance rate (CLCR) ≥ 20 mL/min/1.73m2 as 
determined by the Schwartz (2009) equation at baseline.
Exclusion Criteria
To be eligible for enrollment, a patient must not meet any of the following exclusion criteria:
1.
Known allergy/hypersensitivity to any β-lactam antibacterial;

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2.
History of clinically significant renal, hepatic, or hemodynamic instability (defined as a 
requirement for pharmacological intervention to manage blood pressure in the 24-hour 
window prior to enrollment);
3.
Planned use of cardiopulmonary bypass or dialysis;
4.
Planned blood transfusion within 24 hours of study drug administration; 
5.
Clinically significant abnormal laboratory test results not related to the underlying infection, 
as determined by Investigator;
6.
For Groups 1-5 only:

Height or weight outside of the 5th to 95th percentile; 
7.
Receipt of piperacillin/tazobactam within 24 hours of study drug administration;
8.
Use of any medications known to inhibit tubular secretion of renally-excreted drugs;
9.
Known use of illicit drugs or abuse of alcohol or cigarettes;
10. Patients likely to be at risk of hemodynamic disturbance (as determined by Investigator) 
following collection of the required PK blood samples;
11. Use of any investigational drug or participation in any experimental procedure in the 30 
days preceding study entry.
12. Any condition or circumstance that, in the opinion of the Investigator, would compromise 
the safety of the patient or the quality of study data.
Investigational Product, Dosage and Mode of Administration: 
Single IV dose of ceftolozane/tazobactam based on age and weight infused over 60 (±10) minutes.
The doses below are subject to change (up to a maximum of 30 mg/kg ceftolozane and 15 mg/kg 
tazobactam, not to exceed a fixed dose of 1.5 g ceftolozane/tazobactam) based upon interim analysis 
of PK and safety data:

Group 1 (Ages ≥12  to <18 years): 1.5 g fixed dose of ceftolozane/tazobactam 
(comprising 1000 mg ceftolozane and 500 mg tazobactam)

Group 2 (Ages ≥7 to <12 years): 18 mg/kg ceftolozane and 9 mg/kg tazobactam

Group 3 (Ages ≥2 to <7 years): 18 mg/kg ceftolozane and 9 mg/kg tazobactam

Group 4 (Ages ≥3 months to <2 years): 18 mg/kg ceftolozane and 9 mg/kg tazobactam

Group 5 (Ages birth [>32 weeks gestation, 7 days postnatal]  to <3 months): 12 mg/kg 
ceftolozane and 6 mg/kg tazobactam

Group 6 (Ages birth [≤32 weeks gestation, 7 days postnatal]  to <3 months): 12 mg/kg 
ceftolozane and 6 mg/kg tazobactam
Varying age-appropriate volumes from a fixed concentration, not to exceed 15 mg/mL, of 
ceftolozane/tazobactam will be administered to achieve the intended dose in each pediatric patient.
Duration of Treatment: 
Patients will be screened for eligibility within 48 hours prior to study drug administration and 
monitored at least 24 hours post-dose. 
The patient and/or parent (appropriate legal representative) will be contacted via telephone on Study 
Day 8 (± 2 days) post-infusion for assessment of AEs and concomitant medications and procedures.
Criteria for Evaluation:
Analysis Populations:

Pharmacokinetic (PK) population: All patients who receive one full dose of study drug and 
have blood samples with quantifiable plasma levels at the Cmax (the 1 hour post infusion start 
time point) and at least two time points after Cmax (the 2, 4, or 6 hour post infusion start time 
points), to allow an estimation of area under the concentration versus time curve (AUC).

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
Safety population: All patients who receive any dose (including partial doses) of any study 
medication.
Pharmacokinetics:
Pharmacokinetic data will be summarized by descriptive statistics, including number of 
subjects (n), mean, standard deviation (SD), median, coefficient of variation (CV%), 
minimum, maximum, geometric mean, and geometric CV, and presented for each time point 
by group for plasma concentrations of ceftolozane, tazobactam, and M1.  Individual and 
mean ceftolozane, tazobactam, and M1 plasma concentration-time profiles will be plotted. 
Exploratory analyses may be conducted using graphical and/or regression methods.
The following PK parameters will be determined: maximum plasma concentration (Cmax), time to 
Cmax (Tmax), concentration at last sampling point (Clast), time of last sampling point (Tlast), area under 
the plasma concentration-time curve from 0 to last sample collected (AUC0-last), area under the 
plasma concentration-time curve from 0 to infinity (AUC0-∞), elimination half-life (t1/2), volume of 
distribution at steady state (Vss), and plasma clearance (CL). 
Safety:
Although confounded by the use of other concomitant antibiotics, safety and tolerability 
will be evaluated by examining the incidence, severity, and type of adverse events, changes 
in clinical laboratory tests (including chemistry/hematology, urinalysis, serum creatinine, 
and direct Coombs’ test), and changes from baseline in vital signs. 
The type and incidence of all adverse events and serious adverse events will be tabulated, and events 
occurring within 72 hours of dosing will be analyzed separately. Special attention will be given to 
local tolerability events occurring at time of study drug administration and to those patients who 
discontinue due to an adverse event or a serious adverse event. In addition, hypersensitivity 
reactions, events indicative of hemolytic disorders, and events involving Clostridium difficile will be 
summarized separately. Laboratory data will be summarized by type of laboratory test. Descriptive 
statistics of laboratory values, vital signs and changes from baseline will be summarized. 
Abnormalities detected during the physical examination will be summarized in frequency tables.
Statistical Methods:
Statistical methods are primarily descriptive in nature and will be used to guide decisions as to the 
clinical relevance of findings. No formal statistical analysis is planned.
Safety analyses will include a summarization of exposure, AEs, tabulation of changes from baseline 
in clinical laboratory data and vital signs and concomitant medications.
Characterization of the PK of single dose ceftolozane/tazobactam will be evaluated by analyzing 
plasma concentration data by non-compartmental pharmacokinetic analysis, and generating standard 
pharmacokinetic parameters.  In addition, PK data obtained from all groups will be pooled for a 
population PK analysis, as allowed by the data. These results will be reported separately.

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TABLE OF CONTENTS
SUMMARY OF CHANGES.................................................................................................. 4
SYNOPSIS............................................................................................................................... 6
TABLE OF CONTENTS ..................................................................................................... 11
LIST OF TABLES ................................................................................................................ 15
LIST OF FIGURES .............................................................................................................. 16
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 17
1.0
Introduction............................................................................................................... 20
Ceftolozane/tazobactam ....................................................................................... 20
1.1
Nonclinical Experience......................................................................................... 20
1.2
Safety Pharmacology .......................................................................................... 21
1.2.1
Absorption, 
Distribution, 
Metabolism, 
Excretion, 
and 
Drug-Drug 
1.2.2
Interactions.......................................................................................................... 21
Repeat Dose Toxicity.......................................................................................... 21
1.2.3
Genotoxicity........................................................................................................ 22
1.2.4
Reproductive Toxicity ........................................................................................ 23
1.2.5
Neonatal and Juvenile Development .................................................................. 23
1.2.6
Other Studies....................................................................................................... 24
1.2.7
Clinical Experience with Ceftolozane/tazobactam ............................................ 24
1.3
Pharmacokinetics ................................................................................................ 24
1.3.1
Safety .................................................................................................................. 25
1.3.2
Rationale................................................................................................................ 26
1.4
Study Rationale................................................................................................... 26
1.4.1
Dose Rationale .................................................................................................... 27
1.4.2
2.0
Trial Objectives and Purpose .................................................................................. 27
Primary Objective................................................................................................. 27
2.1
Secondary Objective............................................................................................. 28
2.2
3.0
Investigational Plan .................................................................................................. 28
Overall Study Design............................................................................................ 28
3.1
Dosing and the Interim PK Assessment.............................................................. 29
3.1.1

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Study Visits............................................................................................................ 32
3.2
Study Procedures .................................................................................................. 32
3.3
Clinical Assessments .......................................................................................... 32
3.3.1
Laboratory Assessments ..................................................................................... 33
3.3.2
Pharmacokinetic Sampling ................................................................................. 33
3.3.3
Number of Subjects .............................................................................................. 33
3.4
Treatment Assignment ......................................................................................... 33
3.5
Criteria for Study Termination ........................................................................... 33
3.6
4.0
Selection and Withdrawal of Subjects .................................................................... 35
Subject Inclusion Criteria.................................................................................... 35
4.1
Subject Exclusion Criteria ................................................................................... 36
4.2
Subject Withdrawal Criteria ............................................................................... 37
4.3
Replacement of Patients ....................................................................................... 37
4.4
5.0
Treatment of Subjects............................................................................................... 37
Description of Study Drug ................................................................................... 37
5.1
Concomitant Medications .................................................................................... 37
5.2
Patient Identification and Numbering ................................................................ 38
5.3
6.0
Study Drug Materials and Management ................................................................ 38
Study Drug............................................................................................................. 38
6.1
Study Drug Packaging, Labeling and Storage ................................................... 38
6.2
Study Drug Preparation....................................................................................... 38
6.3
Administration ...................................................................................................... 38
6.4
Study Drug Accountability .................................................................................. 38
6.5
7.0
Pharmacokinetic Assessments ................................................................................. 39
Blood Sample Collection ...................................................................................... 39
7.1
Sample Analysis .................................................................................................... 39
7.2
8.0
Assessment of Safety................................................................................................. 39
Definitions for Adverse Events ............................................................................ 40
8.1
Adverse Events ................................................................................................... 40
8.1.1
Serious Adverse Event........................................................................................ 40
8.1.2
Overdose ............................................................................................................. 41
8.1.3

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Closely Monitored Event .................................................................................... 41
8.1.4
Monitoring of Adverse Events............................................................................. 41
8.2
Monitoring of Laboratory Assessments.............................................................. 42
8.3
Assessment of Adverse Events ............................................................................. 42
8.4
Assessment of Severity ....................................................................................... 42
8.4.1
Assessment of Causality ..................................................................................... 42
8.4.2
Reference Safety Information for the Assessment of Expectedness of AEs ...... 43
8.4.3
Reporting Safety Observations by the Investigator to the Sponsor ................. 43
8.5
Reporting of Nonserious Adverse Events........................................................... 43
8.5.1
Reporting of Drug Exposure During Pregnancy................................................. 43
8.5.2
Reporting of Expedited Safety Observations by the Investigator....................... 44
8.5.3
Expedited Reporting by the Sponsor to the FDA .............................................. 45
8.6
Safety Notifications by the Sponsor to the Investigator .................................... 45
8.7
9.0
Statistical Considerations......................................................................................... 45
Data Collection, Processing and Reporting........................................................ 45
9.1
Population for Analysis ........................................................................................ 46
9.2
PK Population ..................................................................................................... 46
9.2.1
Safety Population ................................................................................................ 46
9.2.2
10.0
Pharmacokinetic Analysis Plan ............................................................................... 46
Primary Endpoint Analysis.................................................................................. 46
10.1
Below Limit of Quantification Values/Missing Values...................................... 46
10.1.1
Pharmacokinetic Parameters............................................................................... 46
10.1.2
Pharmacokinetic/Pharmacodynamic Analysis .................................................... 47
10.1.3
Presentation of Data ............................................................................................. 47
10.2
Pharmacokinetic Data Reporting........................................................................ 47
10.3
Data Displays......................................................................................................... 47
10.4
11.0
Statistical Analysis Plan ........................................................................................... 48
General Methodology ........................................................................................... 48
11.1
Baseline Definitions............................................................................................ 48
11.1.1
Multiple Comparisons/Multiplicity .................................................................... 48
11.1.2
Computing Environment..................................................................................... 49
11.1.3
Subject Disposition ............................................................................................. 49
11.1.4

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Demographics and Baseline Data ....................................................................... 49
11.1.5
Study Drug Exposure.......................................................................................... 49
11.1.6
Secondary Endpoint Analysis ............................................................................. 49
11.1.7
Adverse Events ................................................................................................... 50
11.1.8
Laboratory Data .................................................................................................. 50
11.1.9
Vital Signs.................................................................................................... 51
11.1.10
Concomitant Medications............................................................................ 51
11.1.11
Sample Size and Power Considerations....................................................... 51
11.1.12
Evaluation Criteria....................................................................................... 51
11.1.13
12.0
Direct Access to Source Data/Documents ............................................................... 51
Study Monitoring.................................................................................................. 51
12.1
Protocol Deviations/Amendments ...................................................................... 52
12.1.1
Discontinuation of the Study .............................................................................. 52
12.1.2
Audits and Inspections ......................................................................................... 52
12.2
Institutional Review Board .................................................................................. 53
12.3
13.0
Quality Control and Quality Assurance ................................................................. 53
14.0
Ethics.......................................................................................................................... 53
Ethics Review ........................................................................................................ 53
14.1
Ethical Conduct of the Study............................................................................... 53
14.2
Written Informed Consent................................................................................... 53
14.3
15.0
Data Handling and Recordkeeping ......................................................................... 54
Inspection of Records ........................................................................................... 54
15.1
Retention of Records ............................................................................................ 54
15.2
16.0
Publication Policy...................................................................................................... 54
17.0
References.................................................................................................................. 55

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LIST OF TABLES
Table 1  Ceftolozane/Tazobactam Dosing.............................................................................. 29
Table 2  Schedule of Events.................................................................................................... 34

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LIST OF FIGURES
Figure 1  Study Design ........................................................................................................... 31

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC0-24
Area under the curve from 0 to 24 hours
AUC0-∞
Area under the curve from 0 to infinity
AUCt
Area under the concentration time curve from the 
time of the dose to the  Tlast
β
Beta
BLI
β-lactamase inhibitor 
BLQ
Below limit of quantification 
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
cIAI
Complicated intra-abdominal infections
CL
Plasma clearance
Clast
Last quantifiable plasma concentration
CLCR
Creatinine clearance
Cmax
Maximum concentration
CRO
Contract research organization
Crserum
Serum creatinine
Cubist
Cubist Pharmaceuticals LLC
cUTI
Complicated urinary tract infections
%CV
% Coefficient of variation
CXA-101
Ceftolozane
CXA-201
Ceftolozane/tazobactam
CYP
Cytochrome
CYP450
Cytochrome P450 
DCSI
Developmental Core Safety Information
EC
Ethics Committee

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Abbreviation or 
Specialist Term
Explanation
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic Data Capture
ESBL
Extended spectrum β-lactamase 
ET
Early termination
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
h
Hour 
ICH
International Conference on Harmonization
IP
Intraperitoneal
IRB
Institutional Review Board
IUD
Intrauterine device
IV
Intravenous
kg
Kilogram
L 
Liter
m
Meter
M1
Tazobactam metabolite
MedDRA
Medical Dictionary for Regulatory Activities
µg
Microgram
mg 
Milligram 
MIC
Minimum inhibitory concentration
min
Minute
mL
Milliliter
NOAEL
No observed adverse effect level
PBP
Penicillin-binding protein
PD
Pharmacodynamic
PICC
Peripherally inserted central catheter
PK
Pharmacokinetic
PND
Postnatal day

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Abbreviation or 
Specialist Term
Explanation
PT
Preferred term
PTA
Probability of target attainment
q8h
Every 8 hours
SAE
Serious adverse event
SD
Standard deviation
SOC
System organ class
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½ 
Terminal elimination half-life
t>MIC
Time above the minimum inhibitory concentration
Tmax
Time of maximum concentration
TOC
Test of cure
ULN
Upper limit of normal
Vss
Volume of distribution at steady state 
WBC
White blood count
WHO
World Health Organization 

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1.0 INTRODUCTION
Ceftolozane/tazobactam
1.1
Ceftolozane/tazobactam (formerly known as CXA-201), is a novel antibacterial consisting of 
ceftolozane, a unique antipseudomonal cephalosporin, with tazobactam, a well-established 
beta (β)-lactamase inhibitor (BLI).  Ceftolozane/tazobactam is being developed by Cubist 
Pharmaceuticals, LLC (Cubist) for the treatment of serious bacterial infections in adult 
patients, including complicated urinary tract infections (cUTIs), complicated intra-abdominal 
infections (cIAIs), and nosocomial pneumonia.  Ceftolozane alone was previously referred to 
as CXA-101 or FR264205.
Like other members of the cephalosporin class, ceftolozane exerts its bactericidal activity by 
inhibiting essential penicillin-binding proteins (PBPs), resulting in inhibition of bacterial cell 
wall synthesis and subsequent cell death.  Tazobactam is an inhibitor of most Class A and 
some Class C β-lactamases, with well-established in vitro and in vivo activity in combination 
with active β-lactams.
Ceftolozane displays potent antibacterial activity against common gram-negative and 
selected gram-positive organisms, such as P. aeruginosa, E. coli, K. pneumoniae, 
Enterobacter spp., streptococci, H. influenzae, Moraxella catarrhalis, the majority of 
pathogenic enteric bacilli, and select gram-positive anaerobic species.  Ceftolozane exhibits 
limited activity against staphylococci and enterococci, insufficient for reliable treatment of 
this pathogen.  In general, the gram-positive and gram-negative spectrum of activity of 
ceftolozane is similar to ceftazidime, but the antipseudomonal activity of ceftolozane is the 
most potent among all currently available β-lactams, including the carbapenems.  Most 
importantly, ceftolozane has been shown to be active against strains of P. aeruginosa that are 
resistant to carbapenems, cephalosporins, fluoroquinolones, and aminoglycosides, including 
many multidrug resistant isolates. 
Tazobactam increases the in vitro activity of ceftolozane against the majority of extended 
spectrum β-lactamase (ESBL)-producing gram-negative bacilli and some AmpC 
over-expressing Enterobacteriaceae.  The addition of tazobactam has no significant impact on 
the antipseudomonal activity of ceftolozane, since P. aeruginosa rarely produces ESBLs.  
Both ceftolozane and ceftolozane/tazobactam show time-dependent bactericidal activity 
against various gram-negative organisms, with ceftolozane/tazobactam being more potent 
than piperacillin/tazobactam against Enterobacteriaceae (both ESBL-negative and ESBL-
positive isolates) and P. aeruginosa. 
In summary, ceftolozane is a novel cephalosporin antibiotic which, in combination with the 
potent BLI, tazobactam, has broad-spectrum antibacterial coverage against β-lactam-resistant 
Enterobacteriaceae and multidrug resistant P. aeruginosa.  
Nonclinical Experience
1.2
Ceftolozane/tazobactam has been well characterized in a comprehensive series of in vitro and 
in vivo nonclinical studies that have defined key safety findings, including test-article related 
effects, and the reversibility of these changes.  

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Safety Pharmacology
1.2.1
Ceftolozane showed no potential to affect the functioning of the cardiovascular, respiratory, 
and central nervous systems across rats and dogs at clinically relevant blood concentrations. 
Safety pharmacology studies with tazobactam were not conducted by the Sponsor. The safety
of tazobactam is supported by its long history of clinical use. 
Absorption, Distribution, Metabolism, Excretion, and Drug-Drug Interactions
1.2.2
Ceftolozane and tazobactam, both alone and in combination, exhibited dose-proportional 
intravenous (IV) pharmacokinetics (PK) in rats and dogs with no gender differences and no 
change in systemic exposure with repeat dosing. Ceftolozane was distributed to tissues and 
exhibited low plasma protein binding, a predominantly renal route of elimination, and 
minimal metabolism following IV administration. Tazobactam exhibited low plasma protein 
binding and is metabolized to a single major metabolite, M1, which lacks pharmacologic 
activity. 
No PK interactions were observed between ceftolozane and tazobactam when administered 
to rats or dogs in combination. In vitro, ceftolozane, tazobactam, and the M1 metabolite of 
tazobactam demonstrated low potential for drug-drug interactions involving cytochrome 
(CYP) enzymes and/or transporters at clinically relevant concentrations. 
Repeat Dose Toxicity
1.2.3
No target organ toxicities were identified for ceftolozane alone or in combination with 
tazobactam. Effects associated with ceftolozane and tazobactam treatment alone were 
primarily limited to non-adverse changes in the kidney and liver, respectively. Ceftolozane-
related effects in the kidney were limited to the microscopic presence of hyaline droplets in 
proximal renal tubule epithelium in the absence of toxicologically meaningful degeneration 
or necrosis with no effects on renal function noted as determined by the absence of 
biologically relevant changes in serum blood urea nitrogen (BUN), creatinine, inorganic 
phosphorus, urine volume, or presence of cellular/granular casts [Studies GLR050690 and 
CX.101.TX.031]. A corresponding increase in kidney weight was observed in rats [Studies 
GLR050690 and CX.101.TX.031] but not dogs [Study GLR050729]. The no-observed-
adverse-effect level (NOAEL) for rats was considered 1000 milligram (mg)/kilogram 
(kg)/day, the highest dose level assessed [Studies GLR050690 and CX.101.TX.031and 
Report CX.101.TX.032]. The NOAEL of 300 mg/kg/day for dogs was based on the 
observation of the cephalosporin-induced, histamine-related adverse clinical signs at 1000 
mg/kg/day (namely, flush of the auricular and oral mucosa, swelling of the head, emesis, 
salivation, as well as lateral position and non-kidney-related effects) [Study GLR050729 and 
Report CX.101.TX.032]. Ceftolozane safety margins for cIAI and cUTI based on general 
repeated dose toxicity studies conducted in rats and dogs with ceftolozane alone range from 
approximately 3 fold to 10-fold based on area under the curve (AUC) and approximately 13 
fold to 141-fold based on maximum concentration (Cmax).
The primary effect for tazobactam in rats and dogs was observed in the liver. Microscopic 
evidence of reversible glycogen accumulation was detected in hepatocytes following twice 
daily repeat intraperitoneal (IP) or IV administration of tazobactam to rats [1] and dogs [2], 
respectively, for 6 months at dose levels of 80 and 160 mg/kg/day. A correlating reversible 

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increase in liver weights was evident at 80 and 160 mg/kg/day in rats.  Other reversible 
tazobactam-related effects noted only in rats included a dose-independent increase in food 
consumption in males and females, an increase in reticulocytes in females at 80 and 
160 mg/kg/day, decreased triglycerides in males at 160 mg/kg/day, decreased serum 
triglyceride levels in all females administered tazobactam, and cecal enlargement in females 
at 160 mg/kg/day. Tazobactam administration alone was associated with an increase in 
smooth endoplasmic reticulum and glycogen granules from bile canaliculi and hepatocyte 
nuclei at 160 mg/kg/day in dogs. The NOAEL determined for both species was 40 
mg/kg/day. 
Importantly, no new effects or unexpected toxicities were observed when ceftolozane was 
combined with tazobactam. Ceftolozane safety margins for cIAI and cUTI based on general 
repeated dose toxicity studies conducted in rats and dogs with ceftolozane in combination 
with tazobactam range from approximately 3- to 5-fold based on AUC and approximately 
16- to 41-fold based on Cmax. Tazobactam safety margins for cIAI based on general repeated 
dose toxicity studies conducted in rats and dogs with ceftolozane in combination with 
tazobactam range from approximately 1- to 7-fold based on AUC and approximately 10- to 
15-fold based on Cmax. Tazobactam safety margins for cUTI are not calculated because 
clinical PK data for tazobactam were not collected in cUTI patients.  While modest, the 
tazobactam safety margins support clinical use because tazobactam is a component of a
currently marketed drug (piperacillin/tazobactam) whose mode of action, PK, and safety 
profile has been well characterized and established in animals and humans.
Genotoxicity
1.2.4
The weight of evidence suggests that ceftolozane alone and in combination with tazobactam 
has a low potential for genotoxicity.  
Ceftolozane/tazobactam was negative when tested in a mouse lymphoma assay [Study 
CXA201-T-003] and did not induce the formation of micronucleated erythrocytes in rat bone 
marrow [Study CXA201-T-004]. In an in vitro cytogenetics (Chinese Hamster Ovary cells) 
ceftolozane/tazobactam was positive for structural aberrations at doses ≥ 500/250 microgram 
(μg)/milliliter (mL) for ceftolozane and tazobactam, respectively [Study CXA201-T-002]. 
Ceftolozane was negative when tested in a variety of in vitro assays including a microbial 
mutagenicity assay [Study GLR050752], a chromosomal aberration assay using Chinese 
Hamster Lung fibroblasts [Study GLR050845], and a UDS assay [Study GLR040362]. 
Ceftolozane was positive in a mouse lymphoma assay [Study GLR050528]. Ceftolozane did 
not induce the formation of micronucleated erythrocytes in mouse blood [Study 
GLR050847]. 
Tazobactam was negative in a variety of in vitro assays including a microbial mutagenicity 
assay, a UDS assay, a mammalian point mutation (Chinese hamster ovary cell HPRT) assay, 
a BALB/c-3T3 cell transformation assay, a chromosomal aberration (Chinese hamster lung 
cell) assay [3].  In another mammalian point mutation (mouse lymphoma cell) assay, 
tazobactam was positive [3].  In vivo, tazobactam did not induce the formation of 
micronucleated erythrocytes in rat bone marrow [3].

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Reproductive Toxicity
1.2.5
Standard definitive fertility and embryo/fetal development studies conducted with 
ceftolozane in mice and/or rats have demonstrated that ceftolozane is neither a developmental 
nor reproductive toxicant.
Ceftolozane showed no effect upon fertility or early embryonic development in rats up to 
1000 mg/kg/day, the highest dose level assessed [Study CX.101.TX.002]. The calculated 
area under the curve from 0 to 24 hours (AUC0-24) values associated with this dose are 
approximately 3-fold and 4-fold greater than the mean calculated daily AUC values in cUTI 
and cIAI patients, respectively, receiving the clinically relevant dose of 1000 mg of 
ceftolozane thrice-daily. Studies in rats and mice revealed no embryo/fetal toxicity related to 
ceftolozane administration at doses of up to 1000 and 2000 mg/kg/day, respectively, the 
highest dose tested [Studies CX.101.TX.001 and CXA101.T-006]. The calculated AUC 
from 0 to infinity (AUC0-∞) values associated with this dose range from approximately 4- to 
10-fold greater than the mean calculated daily AUC values in cUTI and cIAI patients 
receiving the clinically relevant dose of 1000 mg of ceftolozane thrice-daily. Administration 
of ceftolozane to pregnant rats from gestation day 6 through lactation day 20 did not affect 
pre or post-natal development of the pups with the exception of a decrease in auditory startle 
response on postnatal day (PND) 60 at maternal doses of 300 and 1000 mg/kg/day [Study 
CX.101.TX.012]. No effect was noted at 100 mg/kg/day. A dose of 300 mg/kg/day is 
associated with a daily AUC value approximately equivalent to the daily clinical exposure 
based on mean daily clinical ceftolozane AUC values for cUTI and cIAI.
Reproduction studies performed with tazobactam in rats revealed no evidence of impaired 
fertility due to tazobactam administered at doses up to 4 times the maximum recommended 
human daily dose based on body-surface area (mg/meter [m]2) [3].  Teratology studies 
performed with tazobactam in mice and rats and have revealed no evidence of harm to the 
fetus due to tazobactam administered at doses up to 8 and 19 times, respectively, the human 
dose based on body-surface area (mg/m2) [3].  Twice daily IP administration to female rats 
for 15 days prior to mating, during the mating, and throughout the gestation and lactation 
period was associated with a decrease in the numbers of implantations and live litter size and 
an increase in the number of still births were evident along with reversible delays in renal 
development at a dose of 640 mg/kg/day following repeat administration to rats [4].  In a 
separate study, twice daily IP administration of tazobactam to female rats from gestation day 
17 through PND 21 at dose levels of 40, 320, and 1280 mg/kg/day was associated with 
decreased pup body weight during the lactation period at doses ≥320 mg/kg/day with an 
increase in stillbirths and a decrease in body weights early postweaning at a dose of 1280 
mg/kg/day [5].  Tazobactam, co-formulated with piperacillin, is currently approved for use in 
pediatric patients down to two months of age. 
Neonatal and Juvenile Development
1.2.6
Once daily subcutaneous administration of ceftolozane/tazobactam to PND4 neonatal 
Sprague Dawley rats for 14 days was associated with clinical observations (decreased motor 
activity, list/impaired righting reflex, ataxia), increased liver and kidney weight, as well as 
microscopic evidence of centrilobular hepatocellular hypertrophy and cytoplasmic 
vacuolation in the proximal convoluted tubular epithelium of the kidney at a dose of 

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1000/500 mg/kg/day [Study CX.101.TX.033]. Hyaline droplets (males only), and basophilic 
tubules and fibrosis in the kidney were also noted at this dose level. A dose of 300/150 
mg/kg/day was associated with increased liver and kidney weight with correlating 
microscopic evidence of centrilobular hepatocellular hypertrophy and cytoplasmic 
vacuolation in the proximal convoluted tubular epithelium of the kidney. No effects were 
observed at a dose of 50/25 mg/kg/day. 
The NOAEL for this study was considered to be 300/150 mg/kg/day, which correlated with 
mean PND17 ceftolozane/tazobactam AUC0-∞and Cmax values of 657/145 µg•h/mL and 
416/184 µg/mL, respectively. Daily ceftolozane and tazobactam exposure values were 
approximately 2-fold greater on day 1 of treatment as compared to day 14.  In a pivotal 28-
day Good Laboratory Practice toxicity study (Study CX.101.TX.038), once daily 
subcutaneous administration of ceftolozane in combination with tazobactam in a 2 to 1 ratio 
to neonatal Sprague-Dawley rats for 28 days (PNDs 4 through 31) was associated with 
clinical observations of decreased motor activity and/or impaired righting reflex at dosages of 
300/150 and 1000/500 mg/kg/day and were considered adverse at 1000/500 mg/kg/day. A 
non-adverse decrease in erythrocytes, hemoglobin, and hematocrit values was noted in male 
and female rats in the 1000/500 mg/kg/day dose group on PND 32.  Non-adverse 
centrilobular hypertrophy of hepatocytes was observed in the 1000/500 mg/kg/day dose 
group.  These effects had reversed or were in the process of reversing following a 28 day 
recovery period. Based on the adverse clinical signs observed at 1000/500 mg/kg/day, the 
NOAEL for this study was considered to be 300/150 mg/kg/day, which correlated with mean 
PND 4 AUClast and Cmax values of 1520/426 µg•h/mL and 525/257 µg/mL, respectively, and 
mean PND 31 AUClast and Cmax values of 296/33.0 µg•h/mL and 294/59.8 µg/mL, 
respectively.    Ceftolozane AUClast and Cmax were approximately 5- and 2 fold lower, 
respectively, on PND 31 as compared to PND 4.  Tazobactam AUClast and Cmax were 
approximately 9- to 15-fold lower and 3- to 4-fold lower, respectively, on PND 31 as 
compared to PND 4.
Other Studies
1.2.7
Ceftolozane showed a potential for local tolerance effects in mice and rats, a low potential for 
antigenicity, and no potential for phototoxicity, immunotoxicity, or hemolytic activity.
Overall, the nonclinical data package collected on ceftolozane/tazobactam supports clinical 
investigation for pediatric use.  Further information is available in the 
ceftolozane/tazobactam Investigator’s Brochure.
Clinical Experience with Ceftolozane/tazobactam
1.3
Ceftolozane alone or ceftolozane/tazobactam has been evaluated in adults in ten completed 
Phase 1 studies, a Phase 2 study in cUTI, a Phase 2 study in cIAI, and two Phase 3 clinical 
studies (one in cUTI and one in cIAI).  A Phase 3 study in nosocomial pneumonia is 
ongoing.
Pharmacokinetics
1.3.1
The results from the adult Phase 1 and Phase 2 studies demonstrated ceftolozane/tazobactam 
PK characteristics are generally consistent with those of other renally-excreted β-lactam 

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antibiotics. Ceftolozane/tazobactam had linear PK across a wide range of doses (250 to 3000 
mg for ceftolozane and 100 to 1500 mg for tazobactam); and its volume of distribution at 
steady state (Vss), approximately 11 to 18 liters (L), was roughly equivalent to the 
extracellular fluid volume. The plasma protein binding was low; approximately 16 to 21% 
and 30% for ceftolozane and tazobactam, respectively. The terminal elimination half-life (t½) 
for ceftolozane and tazobactam was 2 to 3 hours and approximately 1 hour, respectively, 
independent of dose, and with little or no accumulation after multiple dosing every 8 hours or 
every 12 hours. Ceftolozane/tazobactam was primarily cleared from the systemic circulation 
into the urine by glomerular filtration, but tazobactam was also partly cleared by tubular 
secretion. About 20% of the tazobactam dose is converted to a single inactive metabolite 
(M1) via hydrolysis of the β-lactam ring while >95% for ceftolozane was eliminated as 
unchanged parent drug, suggesting minimal potential for cytochrome P450 (CYP450) 
mediated metabolism. Co-administration of ceftolozane/tazobactam given as 1-hour IV 
infusions in a fixed 2:1 ratio of ceftolozane to tazobactam did not change the PK profiles of 
either drug, nor of the tazobactam M1 metabolite. 
Systemic clearance was linearly related to creatinine clearance (CLCR), but no other 
significant intrinsic factors affecting the PK of ceftolozane/tazobactam were identified.  A 
drug-drug interaction study suggested a low potential for any CYP450 or transporter-
mediated PK interaction, and there is a low potential for PK interaction with other drugs 
eliminated primarily by glomerular filtration, such as tobramycin and vancomycin.    
Safety
1.3.2
In adult patients, two Phase 1 and one Phase 2 clinical studies were completed with 
ceftolozane alone, and eight Phase 1, one Phase 2, and two Phase 3 clinical studies in two 
indications were completed with ceftolozane/tazobactam.  A total of 145 subjects in these 
clinical studies received ceftolozane alone, and 1044 received ceftolozane/tazobactam.  
Phase 1 studies suggested ceftolozane/tazobactam was safe and well tolerated.  The most 
common adverse events (AEs) in Phase 1 studies were mainly gastrointestinal in origin 
(nausea, vomiting, constipation and diarrhea), as well as headache and infusion site reactions.  
Multiple dose studies (CXA-101-01, CXA-201-01, and CXA-MD-11-07) demonstrated that 
doses of ceftolozane/tazobactam up to 9000 mg daily (3000 mg every 8 hours [q8h]) were 
well tolerated in adults for durations of up to 10 days.  The thorough QT study (CXA-QT-10-
02) demonstrated at therapeutic and 3-fold supra-therapeutic dose of ceftolozane/tazobactam 
did not increase QTc, QTcF and QTcB intervals, and no findings indicated an effect of 
ceftolozane/tazobactam on cardiac repolarization.  Only one serious adverse event (SAE) was 
reported in the ten Phase 1 studies for ceftolozane or ceftolozane/tazobactam.  One patient in 
study CXA-REN-11-01 reported an unrelated SAE of thrombosis of arteriovenous fistula on 
study day 44, requiring hospitalization for heparinization and catheter replacement.  Adverse 
events leading to discontinuation of ceftolozane/tazobactam in the Phase 1 studies were rare.  
One subject in study CXA-QT-10-02 discontinued due to an unrelated AE of fever, one 
subject in study CXA-MD-11-07 discontinued due to an AE of vomiting assessed by the 
Investigator as related, and one subject in study CXA-EB-13-05 discontinued due to an AE 
of acute drug eruption assessed by the Investigator as related.

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In Phase 2 studies of ceftolozane in cUTI (CXA-101-03) and ceftolozane/tazobactam in cIAI 
(CXA-IAI-10-01), the most common AEs across both studies were pyrexia, nausea, 
constipation, sleep disorder, anemia, headache, vomiting, diarrhea and insomnia.  In study 
CXA-101-03, there was an imbalance in the incidence of hyperglycemia severity grade shifts 
which was neither associated with ongoing abnormalities in serum glucose nor reported as 
adverse events.  In study CXA-IAI-10-01, there was an imbalance in the incidence of 
hemoglobin severity grade shifts in the ceftolozane/tazobactam group; however the decreases 
in hemoglobin appeared to be related to complicated surgical procedures in high-risk subjects 
or the subject’s underlying condition.  Collectively, three subjects experienced a shift from 
negative direct Coombs’ test at baseline to positive at the test of cure (TOC) visit, but none 
were associated with a report of hemolytic anemia.  
No deaths were reported in the ceftolozane/tazobactam treatment arm, and no subjects met 
laboratory criteria for Hy’s rule in study CXA-101-03.  However, in study CXA-IAI-10-01, 
three subjects died in the ceftolozane/tazobactam arm; all were unrelated to study drug and 
occurred following study drug discontinuation.  In the same study, one 
ceftolozane/tazobactam subject met the laboratory criteria for Hy’s rule on therapy.  These 
liver enzyme elevations were likely related to the underlying condition and surgical 
procedure as all levels declined during continued treatment. 
In the integrated Phase 3 studies of ceftolozane/tazobactam in cUTI and cIAI (CXA-cUTI-
10-04, CXA-cUTI-10-05, CXA-cIAI-10-08, and CXA-cIAI-10-09), 1015 adult patients 
received treatment with ceftolozane/tazobactam. The most common AEs from these trials 
were nausea, headache, diarrhea, pyrexia, constipation, hypertension, insomnia, and, 
vomiting.  Overall SAE rates were 5.3% and 5.2% in the ceftolozane/tazobactam and 
comparator arms, respectively. Drug discontinuation rates due to AEs were similar, with 2% 
of patients who discontinued ceftolozane/tazobactam and 1.9% of patients who discontinued 
comparator drug.  Drug-related SAEs with ceftolozane/tazobactam were limited to only two
cases of Clostridium difficile colitis compared to one case with comparator drug. In cUTI, 
there was 1 death in the ceftolozane/tazobactam treatment arm and none in the comparator 
arm.  In cIAI, there were 11 deaths in the ceftolozane/tazobactam arm and 8 deaths in the 
comparator arm.  All of the deaths reported in these Phase 3 studies were deemed unrelated 
to study therapy by the Investigator. 
An open-label Phase 3 study in nosocomial pneumonia was electively terminated by the 
Sponsor after enrollment of 4 patients, in order to devote all resources in initiating and 
completing the larger registration study being conducted as part of the clinical development 
program for nosocomial pneumonia.  Two patients experienced SAEs, 1 in each arm, and the 
1 in the ceftolozane/tazobactam treatment arm resulted in death.  Neither event was deemed 
to be related to study drug.  The Phase 3 registration study in nosocomial pneumonia is 
ongoing.
Rationale
1.4
Study Rationale
1.4.1
This is the first study investigating the use of ceftolozane/tazobactam in pediatric patients. 

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Current guidance documents for pediatric PK studies focus on appropriate dosing in the 
pediatric population based on PK data [6]. The PK of a drug in the pediatric population 
usually cannot be precisely predicted from that in adults. Therefore, PK studies are needed to 
identify the appropriate pediatric dosing.
This study will be conducted to investigate the PK and safety of a single IV dose of 
ceftolozane/tazobactam in pediatric patients from birth to <18 years of age receiving standard 
of care antibiotics either for treatment of suspected or proven gram-negative infection or for 
peri-operative prophylaxis (For Group 6 only, patients will be eligible if receiving antibiotic 
prophylaxis outside of a peri-operative period).  Patients will be recruited into one of six age 
groups.
Dose Rationale
1.4.2
The initial pediatric doses of ceftolozane/tazobactam were chosen based on adult PK data, 
with the objective of achieving the therapeutic exposure levels seen in adults.
Ceftolozane/tazobactam is primarily renally eliminated; therefore, initial doses for each age 
group will take into account the stage of development of their renal function. In each age 
group, an interim analysis of the PK and safety data will be conducted when half of the group 
has received the initially proposed dose. For Groups 5 and 6, an additional interim analysis 
will be conducted after a total of 3 patients across both groups have been dosed. This 
additional interim analysis will only be performed if the first 3 patients span across both 
groups, and will not be required if the first 3 patients are consecutively enrolled into either 
Group 5 or Group 6. Depending on the results of the interim analysis, dosing will either 
continue at the initial dose, or a new optimized dose targeted at achieving the exposure levels 
seen in adult patients.  
The initial dose selected for each group was supported by population PK analysis 
incorporating allometric scaling by body weight and renal function maturation for pediatric 
patients. Monte Carlo simulations were conducted to calculate the probability of target 
attainment (PTA) ≥90% for the PK/pharmacodynamic (PD) driver of approximately 30% 
time above the minimum inhibitory concentration (t>MIC) of 8 g/mL. In addition, these 
simulations restricted the total daily ceftolozane AUC within the limits demonstrated to be 
safe in adults 
(approximately 1100 g*hr/mL). The proposed doses will target a ceftolozane AUC of 
approximately 200 g*hr/mL, similar to the target therapeutic AUC in the adult population.  
Varying age-appropriate volumes of a fixed concentration of ceftolozane/tazobactam will be 
administered intravenously to achieve the intended dose in each pediatric patient. The same 
IV formulation will be used across all age groups.
2.0 TRIAL OBJECTIVES AND PURPOSE
Primary Objective
2.1
The primary objective of this study is to evaluate the PK of a single dose of intravenous 
ceftolozane/tazobactam in pediatric patients from birth to <18 years receiving standard of 
care antibiotic therapy for proven or suspected gram-negative infection, including patients 
receiving peri-operative prophylactic antibiotics.

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Secondary Objective
2.2
The secondary objective of this study is to assess the safety and tolerability of a single dose 
of intravenous ceftolozane/tazobactam in pediatric patients from birth to <18 years receiving 
standard of care antibiotic therapy for proven or suspected gram-negative infection, including 
patients receiving peri-operative prophylactic antibiotics.
3.0 INVESTIGATIONAL PLAN
Overall Study Design
3.1
This is an open-label, non-comparative study of a single IV dose of ceftolozane/tazobactam 
in male and female pediatric patients from birth (7 days postnatal) to <18 years receiving 
concurrent standard of care antibiotic therapy for treatment of proven or suspected gram-
negative infection or peri-operative prophylaxis (For Group 6 only, patients will be eligible if 
receiving antibiotic prophylaxis outside of a peri-operative period). 
Thirty-six eligible patients will be enrolled into one of six age groups (6 patients planned per 
age group): 

Group 1: Ages ≥12 to <18 years 

Group 2: Ages ≥7 to <12 years 

Group 3: Ages ≥2 to <7 years 

Group 4: Ages ≥3 months to <2 years 

Group 5: Ages birth (>32 weeks gestation, 7 days postnatal) to <3 months 

Group 6: Ages birth (≤32 weeks gestation, 7 days postnatal) to <3 months 
The study design, as described in Section 3.1.1 and illustrated in Figure 1, will be used with 
enrollment beginning with Groups 1, 2, 3, and 4. 
In Groups 5 and 6, birth has been defined as at least 7 days postnatal, due to the fact that 
neonatal renal function is closely related to both gestational age and postnatal age. 
Fluctuations in serum creatinine occur in the first week of life and as a result, the Schwartz 
equation, which will be used to calculate renal function in this population, is not 
recommended for use until after the first week of life. Because ceftolozane/tazobactam is 
primarily renally eliminated, it is necessary to limit enrollment in Groups 5 and 6 only to 
those patients who have undergone the fluctuation in serum creatinine observed during the 
first week of life, hence the requirement for 7 days postnatal.  
Subject participation will require a minimum commitment of 6 days and a maximum of 
12 days. Screening assessments will occur within 48 hours of study drug administration (Day 
1). Baseline assessments will be performed following eligibility verification based on 
screening assessments. Patients will be monitored for safety 24 hours post study drug 
infusion. The site will contact the patient and/or parent (or appropriate legal representative) 
via telephone at Study Day 8 (± 2 days) for assessment of AEs and concomitant medications 
and procedures.

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Blood samples for plasma PK determination will be collected in all patients.  Details of the 
PK sample collection procedures can be found in Section 7.1.
Table 2 presents the full Schedule of Assessments.
Dosing and the Interim PK Assessment
3.1.1
All patients will receive a single age and weight-based IV dose of ceftolozane tazobactam as 
a 60 (±10) minute (min) infusion (Table 1). The doses below are subject to change (up to a 
maximum of 30 mg/kg ceftolozane and 15 mg/kg tazobactam, not to exceed a fixed dose of 
1.5 g ceftolozane/tazobactam) based upon interim analysis of PK and safety data.
Table 1  Ceftolozane/Tazobactam Dosing
Age 
Group
Age Range
Ceftolozane/Tazobactam Dosea
(60 (±10) min infusion)
1
≥12 to <18 years
1.5 g fixed dose of ceftolozane/tazobactam
(comprising 1000 mg ceftolozane 
and 500 mg tazobactam)
2
≥7 to <12 years
18 mg/kg ceftolozane and
9 mg/kg tazobactam
3
≥2 to <7 years
4
≥3 months to <2 years
5
Birth (>32 weeks gestation, 
7 days postnatal) to <3 months
12 mg/kg ceftolozane and 
6 mg/kg tazobactam 
6
Birth (≤32 weeks gestation, 
7 days postnatal) to <3 months
a The initial dose is subject to change (up to a maximum of 30 mg/kg ceftolozane and 15 mg/kg tazobactam, not 
to exceed a fixed dose of 1.5 g ceftolozane/tazobactam) based upon interim analysis of PK and safety data. 
In each age group, an interim analysis of PK and safety data will be conducted after 3 
patients have received the initially proposed dose. For Groups 5 and 6, an additional interim 
analysis will be conducted after a total of 3 patients across both groups have been dosed. This 
additional interim analysis will only be performed if the first 3 patients span across both 
groups, and will not be required if the first 3 patients are consecutively enrolled into either 
Group 5 or Group 6. The interim analysis will determine whether this initial dose was 
appropriate based on meeting the following criteria: 

absence of a safety signal (e.g., no SAE that is related to study drug or two reports of 
the same non-serious AE considered to be related to the study drug), and

acceptable target attainment (excluding outliers and including at least 2 out of 3 
patients) for PK/PD driver of approximately 30%T>MIC of 8 g/mL, and 

targeted single dose ceftolozane AUC0-∞of approximately 200 g*hr/mL (which is a 
similar AUC to the proposed clinical adult dose) and does not exceed a steady-state 
ceftolozane AUC of approximately 1100 g*hr/mL total daily exposure (which is the 
maximum exposure that has been previously demonstrated as safe in adults).

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If data from the interim analysis demonstrates that the initially proposed dose meets the 
criteria above, enrollment will continue with the same dose administered to 3 additional 
patients. However, if the interim analysis demonstrates that a new optimized adjusted dose 
(up to a maximum of 30 mg/kg ceftolozane and 15 mg/kg tazobactam, not to exceed a fixed 
dose of 1.5 g ceftolozane/tazobactam) is required, because one or more of the above criteria 
were not met, the new adjusted dose will be administered to 3 additional patients of the same 
age range.
In subsequent groups, the initial dose is also subject to change based upon the results of the 
interim analysis in previous groups. For example, at interim analysis of Group 4 if the 
initially proposed dose results in over or under exposure of study drug, then a new adjusted 
dose will be used for the remainder of the group. In this case, the initially proposed dose in 
Group 5 may also be adjusted, based on the knowledge obtained from the Group 4 interim 
analysis. See Figure 1.
Enrollment of Groups 1-4 will begin at study start. Enrollment of Groups 5-6 will occur 
following interim analysis of Group 4, and will be based on preliminary PK assessments, PK 
variability, and patient safety data.  

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Figure 1  Study Design

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Study Visits
3.2
The schedule of events for the study is summarized in Table 2.
Screening assessments will occur within 48 hours of study drug administration (Day 1). 
Baseline assessments will be performed following eligibility verification based on screening 
assessments. Patients will be monitored for safety 24 (± 6) hours post study drug infusion 
(Day 2). The site will contact the patient and/or parent (or appropriate legal representative) 
via telephone on study day 8 (± 2 days) for assessment of AEs and concomitant medications 
and procedures.
Study Procedures
3.3
The schedule of events for the study is summarized in Table 2.
Clinical Assessments
3.3.1

Full medical and surgical history

Prior and concomitant medications, including those in the mothers of breast-
fed patients, as detailed in Section 5.2

Complete physical examination (Skin, Eyes, Ears/Nose/Throat, Head/Neck, 
Chest, Heart/Vascular, Abdomen, Neurological [sensory and motor], 
Musculoskeletal, and Extremities)

Vital sign assessment including blood pressure, heart rate, respiratory rate and 
temperature (oral, axillary, tympanic, forehead or core)

Height and weight 

12-lead electrocardiogram (ECG)

In the event a patient is being continuously monitored with a 
cardiorespiratory monitor, an ECG waveform printout may be used

Estimate the patient’s CLCR using the patient’s serum creatinine (Crserum) 
value (mg/dL), height (cm), and the appropriate Schwartz (2009) equation:
Glomerular filtration rate [GFR] (mL/min per 1.73 m
2) = 0.413 * 
height/Crserum

Concomitant procedures

Assessment of AEs, as detailed in Section 8.0, with a separate assessment of 
infusion-related reactions on Day 1

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Laboratory Assessments
3.3.2

Blood samples for hematology (hemoglobin, hematocrit, white blood cell 
[WBC] count with differential, and platelet count), serum chemistry (alkaline 
phosphatase, albumin, blood urea nitrogen [BUN], creatinine, non-fasting 
serum glucose, potassium, alanine aminotransferase, aspartate 
aminotransferase, sodium, total bilirubin, total protein) and coagulation 
(prothrombin time) evaluation

Blood sample for direct Coombs’ test

Serum pregnancy test for female patients who have undergone menarche

Urinalysis from patients who are either toilet trained and able to provide a 
specimen, catheterized, or fitted with a urine collection bag
For patients less than 3 months of age (Groups 5 and 6), study-specific blood draws for 
coagulation (prothrombin time) and the direct Coombs’ test should be done at the discretion 
of the investigator based on safety and risks to the patient. 
Pharmacokinetic Sampling 
3.3.3

Collect blood samples as detailed in Section 7.1.
Number of Subjects
3.4
Thirty-six patients are planned to be enrolled, with 6 patients planned in each of the 6 age 
groups: ≥12 to <18 years, ≥7 to <12 years, ≥2 to <7 years, ≥3 months to <2 years, birth (>32 
weeks gestation, 7 days postnatal) to <3 months, and birth (≤32 weeks gestation, 7 days 
postnatal) to <3 months.  
Treatment Assignment
3.5
All patients will receive a single IV dose of ceftolozane/tazobactam on Day 1. 
Criteria for Study Termination
3.6
The Sponsor reserves the right to terminate the study at any time. Reasons for termination at 
any particular site includes, but are not limited to, the following: safety or AE finding that 
poses a potentially significant risk to the patients, site non-compliance with protocol and 
regulatory requirements, institutional review board (IRB)/ethics committee (EC) or the 
Investigator’s decision to terminate or suspend the study at the investigative site. 

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Table 2  Schedule of Events
Procedure
Screeninga
Study Day 1
Study Day 2b
or Early Termination
Study Day 8c
(Follow-up)
Informed Consent and Minors’ Assent d
X
Medical/Surgical and Medication History e
X
Inclusion/Exclusion
X
Safety
Physical Examination
X
Xf
X
Vital Signs 
Xg
Xh
X
Serum Pregnancy Test i
X
ECG j
X
Xk
Chemistry/Hematology l
X
X
Direct Coombs’ Test l
X
X
Urinalysis m
X
Concomitant Medications and Procedures
X
X
X
X
Adverse Event Assessment
X
X
X
Assessment of Infusion-Related Reactions
Xk
Pharmacokinetics
Ceftolozane/tazobactam Administration
X
Plasma PK Sampling (venous or arterial samples) n
X
ECG: electrocardiogram; PK: pharmacokinetic
a.
With the exception of Informed Consent and Minors’ Assent, all must be completed within 48 hours prior to dosing. 
b.
Study Day 2 evaluations to occur 24 (± 6) hours after completion of study drug infusion.
c.
Site to contact patient and/or parent (or appropriate legal representative) via telephone on Study Day 8 (± 2 days). 
d.
Written parental (or appropriate legal representative) informed consent and age-appropriate assent.
e.
Includes medication history of the mothers of breast-fed patients. 
f.
Physical examination before dosing. 
g.
Includes height and weight.
h.
Vital sign assessments (blood pressure, heart rate, and temperature [oral, axillary, tympanic, forehead or core]) will be conducted within 2 hours prior to dosing and 
within 15 minutes after the end of the ceftolozane/tazobactam infusion.
i.
For female patients who have undergone menarche. 
j.
If a patient is being continuously monitored with a cardiorespiratory monitor, an ECG waveform printout may be used
k.
To be conducted on Study Day 1 after completion of study drug infusion 
l.
For patients less than 3 months of age (Groups 5 and 6), study-specific blood draws for coagulation (prothrombin time) and the direct Coombs’ test should be done at 
the discretion of the investigator based on safety and risks to the patient
m.
Urine will be collected from patients who are either toilet trained and able to provide a specimen, catheterized, or fitted with a urine collection bag.
n.
PK blood samples will be collected at up to the following six time points: 0 h, 0.5 h (± 5 minutes), 1 h (end of the study drug infusion + 5 minutes), 2 h (± 10 minutes), 
4 h (± 10 minutes), 6 h (± 20 minutes) after start of infusion. In the youngest pediatric patients (<3 months), PK samples will be collected at the following three time 
points: 1 h (end of the study drug infusion + 5 minutes), 2 h (± 10 minutes), 6 h (± 20 minutes) after start of infusion

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4.0 SELECTION AND WITHDRAWAL OF SUBJECTS
Subject Inclusion Criteria
4.1
To be eligible for enrollment, a patient must fulfill all of the following inclusion criteria:
1. Provide written parental (or appropriate legal representative) informed consent and 
age-appropriate assent prior to any study-related procedure not part of normal 
medical care;
2. Male or female from birth (defined as at least 7 days postnatal) to  <18 years of age; 
3. Able to comply with the protocol for the duration of the study;
4. For female patients who have undergone menarche:

Is not pregnant (as confirmed by the serum pregnancy test at Screening) and 
not planning to become pregnant within 30 days of last study drug 
administration, AND 

Is non-lactating, AND

Is abstinent OR utilizes one of the following for at least 1 month prior to 
screening: hormonal contraceptives (injectable, oral, patch, or vaginal ring), 
intrauterine device (IUD), or barrier method (diaphragm).  This method must 
be used in combination with a barrier method of contraception for their male 
partner (condom). Patients must be willing to practice these methods for at 
least 30 days after study drug administration;
5. For male patients who are sexually active with female partners who have undergone 
menarche: patient must be using and willing to continue using medically acceptable 
forms of contraception (abstinence, or male condom for patients plus an additional 
method of contraception for their female partners) from Screening and for at least 30 
days after study drug administration;  
6.
For Groups 1-5:

Receiving standard of care antibiotic therapy for suspected or diagnosed 
gram-negative infection or for peri-operative prophylaxis;
For Group 6:

Receiving standard of care antibiotic therapy for suspected or diagnosed 
gram-negative infection or as antibiotic prophylaxis;
7. For Groups 1-4: 

Have a calculated creatinine clearance rate (CLCR) ≥ 80 mL/min/1.73m2 as 
determined by the Schwartz (2009) equation at baseline.

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For Group 5: 

Have a calculated creatinine clearance rate (CLCR) ≥ 50 mL/min/1.73m2 as 
determined by the Schwartz (2009) equation at baseline.
For Group 6:

Have a calculated creatinine clearance rate (CLCR) ≥ 20 mL/min/1.73m2 as 
determined by the Schwartz (2009) equation at baseline.
Subject Exclusion Criteria
4.2
To be eligible for enrollment, a patient must not meet any of the following exclusion criteria:
1. Known allergy/hypersensitivity to any β-lactam antibacterial;
2. History of clinically significant renal, hepatic, or hemodynamic instability (defined as 
a requirement for pharmacological intervention to manage blood pressure in the 24-
hour window prior to enrollment);
3. Planned use of cardiopulmonary bypass or dialysis;
4. Planned blood transfusion within 24 hours of study drug administration; 
5. Clinically significant abnormal laboratory test results not related to the underlying 
infection, as determined by Investigator;
6. For Groups 1-5 only:

Height or weight outside of the 5th to 95th percentile; 
7. Receipt of piperacillin/tazobactam within 24 hours of study drug administration;
8. Use of any medications known to inhibit tubular secretion of renally-excreted drugs;
9. Known use of illicit drugs or abuse of alcohol or cigarettes;
10. Patients likely to be at risk of hemodynamic disturbance (as determined by 
Investigator) following collection of the required PK blood samples;
11. Use of any investigational drug or participation in any experimental procedure in the 
30 days preceding study entry.
12. Any condition or circumstance that, in the opinion of the Investigator, would 
compromise the safety of the patient or the quality of the study data.

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Subject Withdrawal Criteria
4.3
Patients may withdraw from the study at any time without prejudicing their medical care and 
are not obliged to state their reasons. In addition, patients may be withdrawn, if deemed 
necessary for their health and safety, by the Investigator or the Sponsor. Subjects that 
discontinue for any reason should be asked to provide the reason(s) for discontinuation, and 
assessments should be performed as outlined in the Schedule of Assessments for Study Day 
2/Early Termination [ET] visit (Table 2).  Reasons for withdrawal from the study will be 
summarized. Any discontinuations must be fully documented in the electronic case report 
form (eCRF).
Replacement of Patients
4.4
Patients who are withdrawn from the study before receiving the full dose of 
ceftolozane/tazobactam or with insufficient samples to be eligible for the PK analysis may be 
replaced in order to enroll a total of 36 PK evaluable patients. Patient identification numbers 
will not be reused.
5.0 TREATMENT OF SUBJECTS
Description of Study Drug
5.1
Study medication will be supplied by the Sponsor for use in this protocol and is for 
investigational use only.  Please refer to the current Investigator’s Brochure for additional 
information.
Product Name:
ceftolozane/tazobactam
Dosage Form:
IV infusion over 60 (±10) minutes
Route of Administration:
Intravenous
Physical Description:
When a 1.5 g dose of ceftolozane/tazobactam lyophilized 
powder is reconstituted and diluted into an IV bag for use, 
ceftolozane/tazobactam contains 1000 mg of active 
ceftolozane and tazobactam sodium at a quantity equivalent 
of 500 mg of tazobactam free acid. Inactive ingredients 
include sodium chloride as a stabilizer and L-arginine and 
citric acid for pH adjustment.
Manufacturer:
Cubist Pharmaceuticals, LLC
Concomitant Medications
5.2
All medications given, to the patient and to the mothers of breast-fed patients, within 7 days 
prior to the first dose of study drug through the last study evaluation (Study Day 8) must be 
recorded in the appropriate section of the eCRF.    

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The use of piperacillin/tazobactam or any medication that is known to inhibit the tubular 
secretion of renally excreted drugs within 24 hours of study drug administration is prohibited 
(for example: piperacillin, probenecid, cimetidine, diclofenac, indomethacin, mycophenolate, 
olmesartan).
Patient Identification and Numbering
5.3
At time of consent, patients will receive a unique identification number specific to the site. 
The full Patient Identification Number will consist of a three-digit site number and a four-
digit patient number separated by a hyphen (e.g.: XXX-XXXX).  The first digit of the four-
digit patient number will represent the patient’s age group (1-6).  For example, Age Group 1 
will begin with 1001, Age Group 2 will begin with 2001, Age Group 3 will begin with 3001, 
Age Group 4 will begin with 4001, Age Group 5 will begin with 5001, and Age Group 6 will 
begin with 6001.
6.0 STUDY DRUG MATERIALS AND MANAGEMENT
Study Drug
6.1
Study medication will be supplied by the Sponsor for use in this study and is for 
investigational use only.
Study Drug Packaging, Labeling and Storage
6.2
Labeling and packaging of study medication will meet applicable regulatory requirements. 
Study medication must be stored in a secure, limited access area, and may be dispensed only 
by specifically authorized personnel. Refer to the Pharmacy Manual for further details on 
packaging, labeling, and storage.
Study Drug Preparation
6.3
Refer to the Pharmacy Manual for step-by-step directions for ceftolozane/tazobactam 
preparation.
Administration
6.4
Patients will receive a single IV dose of ceftolozane/tazobactam as a 60 (±10) minute IV 
infusion.  Varying age-appropriate volumes from a fixed concentration, not to exceed 15 
mg/mL, of ceftolozane/tazobactam will be administered to achieve the intended dose in each 
pediatric patient. This approach will minimize the infusion volume in younger groups. 
Infusion rates will differ based on the volume of each dose in each patient.
Study Drug Accountability
6.5
The site will maintain accurate inventory and dispensing records. Unused study medication 
must not be discarded nor used for any purpose other than the present study. The study 
monitor will review the drug accountability forms prior to arranging for return or destruction 
of all study medication. Refer to the Pharmacy Manual for further details on study drug 
accountability.

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7.0 PHARMACOKINETIC ASSESSMENTS
For complete details and timing of procedures and assessments, please refer to the Schedule 
of Assessments (Table 2).
Blood Sample Collection
7.1
Blood samples (at least 0.5 mL per sample) for plasma PK determination of ceftolozane, 
tazobactam, and tazobactam M1 plasma levels will be collected in all patients.  
For patients in Groups 1-4 (>3 months of age), samples will be collected at up to the 
following six time points: 0 h, 0.5 h (± 5 minutes)*, 1 h (end of the study drug infusion + 5 
minutes), 2 h (± 10 minutes), 4 h (± 10 minutes), and 6 h (± 20 minutes) after the start of 
infusion.  
* Collection of the 0.5 hour time point sample is optional in cases where a second IV 
line (or comparable means of access) is not available.
For patients in Groups 5-6 (<3 months of age), samples will be collected at the following 
three time points: 1 h (end of the study drug infusion + 5 minutes), 2 h (± 10 minutes), and 6 
h (± 20 minutes) after the start of the infusion.  
NOTE: The 1 hour time point is equivalent to the end of the study drug infusion. This 
PK blood sample should be taken just after the total dose is administered and the 
infusion line is flushed with 2-3 mL of normal saline or per site standard of care. 
The method of sampling for PK blood draws is at the discretion of the Investigator 
(e.g., peripherally inserted central catheter [PICC] line, indwelling catheter access, individual 
peripheral phlebotomies, peri-operatively placed arterial line). Samples taken via an IV line 
(or comparable means of access) are preferred, however, in instances where samples are 
unable to be obtained from a second line, alternative methods (such as heel sticks or finger 
sticks) are allowed.  
In circumstances in which the blood draw and study medication infusion must occur in the 
same limb, the blood must be drawn more distally in the vein (approximately 3-5 inches) 
from the infusion site.
In cases where obtaining a second IV line (or comparable means of access) is unsuccessful, a 
single IV line (or comparable means of access) is acceptable for both drug administration and 
sample collection at the 0, 1 (end of infusion), 2, 4, and 6 hour time points. Prior to obtaining 
PK samples, the line must be flushed with 2-3 mL of normal saline or per site standard of 
care to ensure the total dose is administered. 
Sample Analysis
7.2
Refer to the Laboratory Manual for directions for sample analysis.
8.0 ASSESSMENT OF SAFETY
Safety will be assessed through collection of AEs, laboratory evaluations (hematology, 
chemistry and coagulation), vital signs, and physical examinations.

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Adverse events and SAEs will be collected from administration of the first dose of study 
medication through the last study contact.
Definitions for Adverse Events
8.1
Adverse Events
8.1.1
An AE is any untoward medical occurrence in a patient or clinical trial subject administered 
a pharmaceutical product that does not necessarily have to have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product.

Adverse events may be new events or may be pre-existing conditions that have 
become aggravated or have worsened in severity or frequency.

Adverse events may be clinically significant changes from baseline in laboratory tests 
or other diagnostic investigations, and abnormal physical examination findings.
Pregnancy is not an AE; however, if a subject or female partner of a male subject becomes 
pregnant during the conduct of the study, the Investigator must notify the Sponsor according 
to the procedures in Section 8.5.2.
Serious Adverse Event
8.1.2
An SAE is any adverse experience occurring at any dose that results in any of the following 
outcomes:

Death;

Life-threatening experience;

Note:  “Life-threatening” refers to a situation in which the subject was at risk of 
death at the time of the event. It does not refer to an event which might have 
caused death if it were more severe;

Requires inpatient hospitalization or prolongation of existing hospitalization;

Note:  Adverse events requiring hospital admissions that are less than 24 hours in 
duration do not meet this criterion.  A scheduled hospitalization for a pre-existing 
condition that has not worsened during participation in the study does not meet 
this criterion.  Pre-planned hospitalizations for an elective medical/surgical 
procedure or routine check-ups do not meet this criterion;

Results in persistent or significant disability or incapacity;

Is a congenital anomaly or birth defect;

Is considered to be an important medical event.
Note:  Important medical events are those that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or 
may require intervention to prevent one of the outcomes listed in the definition 
above.

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Overdose
8.1.3
For this study, an overdose of ceftolozane/tazobactam is considered to be any dose that is 
higher than the protocol-specified dose for the patient’s age group. Any overdose must be 
reported to the Sponsor as described in Section 8.5.
Closely Monitored Event
8.1.4
A closely monitored event is a non-serious AE or occurrence that is designated to be an event 
of special interest which must be reported to the Sponsor as though it were a SAE as 
described in Section 8.5.
The following events are considered closely monitored for this trial:

Any of the following abnormal laboratory parameters or clinical findings suggesting 
unacceptable hepatic toxicity (Hy’s Law criteria):
o
Alanine aminotransferase (ALT)  or aspartate aminotransferase (AST) > 8 x 
upper limit of normal (ULN)
o
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN or INR > 1.5
o
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 
5%).
Serum ALT, AST, alkaline phosphatase, total bilirubin and/or INR values are to be measured 
every 48-72 hours and repeated until medically stable. These data should also be reported to 
the Sponsor as follow-up information as described in Section 8.5.
If the site cannot identify an alternative etiology for these laboratory abnormalities, these test 
results should be reported as an SAE.  The causality will be assessed as related to study drug, 
either by the Investigator or the Sponsor.  Hy’s Law cases that meet any seriousness criteria 
should be reported as SAEs as they require expedited reporting to authorities like Suspected 
Unexpected Serious Adverse Reactions (SUSARs) as per local regulatory requirements.  
Monitoring of Adverse Events
8.2
Each subject will be monitored for the occurrence of AEs, including SAEs, beginning 
immediately after administration of the first dose of study medication.  Each subject will be 
followed for safety monitoring until the last follow-up visit in the trial as described in the 
schedule of events (see Table 2).
Subjects will be questioned and/or examined by the Investigator or a qualified designee for 
evidence of AEs.  The questioning of subjects with regard to the possible occurrence of 
adverse events will be generalized such as, “How have you been feeling since your last 
visit?”  The presence or absence of specific AEs should not be elicited from subjects.
Subjects having AEs will be monitored with relevant clinical assessments and laboratory 
tests, as determined by the Investigator.

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Adverse events, actions taken as a result of AEs, and follow-up results must be recorded in 
the eCRF, as well as in the subject’s source documentation.  Follow-up laboratory results 
should be filed with the subject’s source documentation.
For all SAEs and AEs that require the subject to be discontinued from the trial, relevant 
clinical assessments and laboratory tests will be repeated as clinically appropriate, until final 
resolution or stabilization of the event(s).
Monitoring of Laboratory Assessments
8.3
All laboratory assessments will be performed at a local laboratory.  The clinical laboratory 
values will be reported to the Investigator who will review them for clinical significance and 
consideration as an AE.
Assessment of Adverse Events
8.4
Assessment of Severity
8.4.1
The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe nausea).  This is not the same as 
“serious,” which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject’s life or functioning.  The severity of AEs will be 
assessed according to the following definitions:

Mild:  the AE is noticeable to the subject and/or the Investigator, but does not 
interfere with routine activity.

Moderate:  the AE interferes with routine activity, but responds to symptomatic 
therapy or rest.

Severe:  the AE significantly limits the subject’s ability to perform routine activities 
despite symptomatic therapy.
Assessment of Causality
8.4.2
A medically-qualified Investigator must assess the relationship of any AE (including SAEs) 
to the use of a study drug, as related or not related, based on clinical judgment and using all 
available information, and may include consideration of the following factors:

Possible alternative causes of the AE, including the disease under treatment, pre-
existing conditions, concomitant use of other drugs, and presence of environmental or 
genetic factors.

The temporal association between drug exposure and onset of the AE. 

Whether the manifestations of the AE are consistent with known actions or toxicity of 
the investigational product.

Dechallenge:  the AE resolved or improved with stopping use of the investigational 
product.  Judgment should be used if multiple products are discontinued at the same 
time.

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
Rechallenge:  the AE recurred or worsened upon re-exposure to the investigational 
product. 
The causal relationship between a study drug and the AE will be assessed using one of the 
following categories:
Not Related:  An AE is not associated with study drug if: 

Temporal relationship is lacking (e.g., the event did not occur within a reasonable 
time frame following administration of the study medication); or

Other causative factors more likely explain the event (e.g., a pre-existing condition, 
other concomitant treatments); or

Dechallenge was either not clinically indicated or did not result in clinical 
improvement; or

AE did not reoccur upon rechallenge (if applicable).
Related: An AE is attributed to the study drug if: 

There is a positive temporal relationship (e.g., the event occurred within a reasonable 
time frame following administration of study medication); and

The AE is more likely explained by the investigational product than by another cause 
(i.e., the AE shows a pattern consistent with current knowledge of the investigational 
product or the class of the investigational product), or 

The event resolved on dechallenge 

The event re-occurred upon rechallenge (if applicable).
Reference Safety Information for the Assessment of Expectedness of AEs
8.4.3
The Reference Safety Information (RSI) for assessing the expectedness of an adverse event 
for ceftolozane/tazobactam in this trial can be found in the Developmental Core Safety 
Information (DCSI) section of the most recent Investigator’s Brochure for 
ceftolozane/tazobactam.
Reporting Safety Observations by the Investigator to the Sponsor
8.5
Reporting of Nonserious Adverse Events
8.5.1
All AEs, regardless of seriousness, severity, or causal relationship to study medication, will 
be recorded on the AE page of the eCRF.  
Reporting of Drug Exposure During Pregnancy
8.5.2
If the subject or the female partner of a male subject becomes pregnant after receiving study 
medication during the course of study, the Investigator must report this to Merck 
Pharmacovigilance using the Pregnancy Reporting Form within 24 hours of becoming aware 
of the event. 

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If the female partner of a male subject becomes pregnant, the Investigator must attempt to 
obtain consent to collect pregnancy information (including the status of the newborn, if 
applicable) before reporting information to the Sponsor.
If not all information on the Pregnancy Reporting Form is available at the time of the initial 
report, follow-up Pregnancy Reporting Forms will be completed and submitted within 24 
hours of becoming aware of new information.  The Investigator is required to attempt follow-
up on the pregnancy until the completion of the pregnancy.  The outcome of the pregnancy 
and the status of the newborn (if applicable) will be reported on the Pregnancy Reporting 
Form within 24 hours of the Investigator becoming aware.
Reporting of Expedited Safety Observations by the Investigator
8.5.3
Any occurrence of the following events or outcomes in a subject in the trial must be reported 
within 24 hours of becoming aware of the event by the Investigator or qualified designee to 
the Merck Pharmacovigilance department:

SAE;

Pregnancy;

Overdose

Closely monitored events
The investigator is to report any Expedited Safety Observations from the list above to Merck 
Pharmacovigilance using the appropriate reporting form within 24 hours of becoming aware 
of the event. 
Any observation reported to Merck Pharmacovigilance that is also an AE is to be recorded in 
the eCRF, as well as in the subject's source documentation along, with any actions taken. If 
not all information is available at the time of the initial report, follow-up reports will be 
completed and submitted.  
The Investigator is required to follow SAEs until resolution regardless of whether the 
subjects are still participating in the study.  Resolution is defined as:

Resolved with or without residual effects (sequelae);   

A return to baseline for a pre-existing condition;

The Investigator does not expect any further improvement or worsening of the event; 

Fatal outcome: If an autopsy is performed on a deceased subject, the autopsy report 
must be provided to the sponsor as soon as it is available.
PPD
PPD

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Expedited Reporting by the Sponsor to the FDA
8.6
Merck Pharmacovigilance will monitor the data for safety. All SAEs that are considered 
unexpected and related to the study agent (SUSAR) will be reported by the Sponsor or 
designee as expedited (i.e., 7/15-Day) reports to the United States Food and Drug 
Administration (FDA) and to all participating investigators.  In addition, the Sponsor or 
designee follows all applicable local and national regulatory requirements regarding safety 
reporting.  Each investigator must also comply with the applicable regulatory requirements 
related to the reporting of SAEs to the IRB responsible for reviewing the study at their site.
Safety Notifications by the Sponsor to the Investigator
8.7
Investigators will receive prompt notification of any adverse experience associated with the 
use of the study medication that is both serious and unexpected, or any finding that suggests 
a significant risk for subjects.  The Investigator will promptly inform the IRB of the 
notification and insert the notification in the Investigator’s Regulatory Binder in accordance 
with local regulations.
9.0 STATISTICAL CONSIDERATIONS
Data Collection, Processing and Reporting 
9.1
The site will be supplied with the following data collection tool:  a web browser address for 
an Electronic Data Capture (EDC) system database that has been fully validated and 
conforms to 21 Code of Federal Regulations (CFR) Part 11 and the Guidance for Industry on 
Computerized Systems Used in Clinical Trials requirements.  The EDC system database will 
be maintained by a Contract Research Organization (CRO). 
The trained Investigator site staff will enter the data required by the protocol into the eCRFs 
from source documents (e.g., medical records and study-specific data capture forms as 
needed) into the EDC system.  All information on the eCRFs must be traceable to these 
source documents.  Data recorded directly on the eCRFs will be defined before study start. 
eCRFs will be completed for all patients.  Informed consent, demography, 
inclusion/exclusion and end of study eCRF pages are needed for patients who are enrolled 
but not treated.  A clinical monitor will review the eCRFs entered by investigational staff for 
completeness and accuracy.
Automatic validation programs or manual checks for data discrepancies in the eCRFs may 
result in electronic queries generated for resolution by the investigational site.  Designated 
investigator site staff is required to respond to these queries and make any necessary changes 
to the data.  
All treatment-emergent AEs (events occurring from the first dose of study medication 
through the last study evaluation) will be recorded.  Medical and surgical history and AEs 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. 

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Audits for quality assurance of the database may be performed according to relevant 
Standard Operating Procedures within the CRO or at the request of the Sponsor’s Quality 
Assurance department.
Population for Analysis
9.2
PK Population
9.2.1
The PK population will include patients who receive one full dose of study drug and have 
blood samples with quantifiable plasma levels at the Cmax (the 1 hour post infusion start time 
point) and at least two time points after Cmax (the 2, 4, or 6 hour post infusion start time 
points), to allow an estimation of area under the concentration versus time curve (AUC).
Safety Population
9.2.2
The Safety population will include patients who receive any dose (including partial doses) of 
any study medication.
10.0 PHARMACOKINETIC ANALYSIS PLAN
A Pharmacokinetic Analysis Plan with further details will be prepared, and will be finalized 
before database lock and analysis of the data.
Primary Endpoint Analysis
10.1
The primary endpoints are AUC and Cmax for ceftolozane, tazobactam and the M1 metabolite 
of tazobactam as data allow.
Below Limit of Quantification Values/Missing Values
10.1.1
All pre-dose below limit of quantification (BLQ) values in period 1 will be set to zero. 
Missing or BLQ values obtained after the first quantifiable concentration will be replaced by 
a period. 
Sampling Times
Actual blood draw times will be used to calculate PK parameters.  For the final analysis, 
tables for the PK calculations will be based on actual times.
Pharmacokinetic Parameters
10.1.2
The pharmacokinetic parameters will be determined by non-compartmental pharmacokinetic 
analysis.  The PK parameters for all analytes (ceftolozane, tazobactam and M1 metabolite of 
tazobactam, except as noted below) may include but are not limited to:

Cmax – Maximum observed plasma concentration over the entire sampling interval

tmax – Time of Cmax

Clast – Last quantifiable plasma concentration

Tlast – Time of Clast

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
AUCt –  Area under the concentration time curve from the time of the dose to the  
Tlast (single dose)

AUC0-∞– Area under the concentration versus time curve from zero to infinity 
(single dose)

t½ – Half-life

Vss – Volume of distribution at steady state (ceftolozane and tazobactam only)

CL – Plasma clearance (ceftolozane and tazobactam only)
If PK data are sparse, alternate PK data analysis methodology such as non-compartmental 
analysis based on a composite profile may be used. 
In addition, PK data obtained from all groups will be pooled for a population PK analysis, as 
allowed by the data. These results will be reported separately.
Pharmacokinetic/Pharmacodynamic Analysis
10.1.3
The PK/PD (exposure-safety) analysis may be explored if any trends are observed.  
Exploratory analyses may be conducted using graphical and/or regression methods.
Presentation of Data
10.2
Data will be presented in tables and listings.  Listings may include but are not limited to:  
subject ID, dose administered, body weight, drug concentrations, time points and individual 
derived PK parameters.  Summary tables may include but are not limited to the number of 
subjects, arithmetic means, standard deviations (SD), % coefficient of variation (%CV), 
minimum, median and maximum values, and geometric mean for individual parameters.
Pharmacokinetic Data Reporting
10.3
The clinical study report will provide the following information:

Deviations from described PK analysis, if any

Results and discussion of the pharmacokinetic parameters

Study conclusions
Data Displays
10.4
Data displays may include but are not limited to:
In-text tables

Summary statistics (n, mean, %CV, median, min-max and geometric mean) of PK 
parameters Dose and age groups

Summary statistics (n, mean, %CV, median, min-max and geometric mean) of 
plasma concentration-time values by Dose and age groups

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In-text graphs

Mean plasma concentration time profiles (with error bar) by Dose and age groups

AUC and Cmax box plots by Dose and age groups
Appendix

Individual plasma concentration-time profiles (linear-linear and log-linear) 

Summary statistics (n, mean, SD, %CV, median, min, max and geometric mean) 
for plasma concentration-time data by Dose and age groups

Listing of individual pharmacokinetic parameters by subject, age group, and dose 

Summary statistics (n, mean, SD, %CV, median, min, max and geometric mean) 
of pharmacokinetic parameters by Dose and age groups
11.0 STATISTICAL ANALYSIS PLAN
A Statistical Analysis Plan with further details will be prepared, and will be finalized before 
database lock and analysis of the data.
General Methodology
11.1
The safety and tolerability of single IV doses ceftolozane/tazobactam in pediatric patients 
from birth to <18 years will be evaluated in the Safety population.  Descriptive statistics for 
continuous variables will include number of subjects, mean, standard deviation, median, 
minimum and maximum.  Categorical variables will include number and percent of the 
subjects in each category.  Adverse event data will be tabulated by age group and dose (if not 
all subjects received the same dose).   Clinical laboratory data will be presented at baseline 
and at study Day 2.  Vital signs data will be presented at baseline, Day 1, and Day 2.
A subanalysis of Groups 5 and 6 will be conducted in patients aged 7 to 28 days and those 
aged 29 days to < 3 months.
Descriptive statistics will be used to guide decisions as to the clinical relevance of findings.  
No formal hypothesis tests are planned. Table and listing shells will be provided in a separate 
document.
Baseline Definitions
11.1.1
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug, unless otherwise specified.
Multiple Comparisons/Multiplicity
11.1.2
Multiplicity is not of concern for this study with a descriptive interpretation of PK and safety 
endpoints.  No formal statistical hypotheses testing will be performed.

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Computing Environment
11.1.3
All statistical analyses will be performed using SAS statistical software Version 9.1.3., unless 
otherwise noted.  Adverse events will be coded using the MedDRA. Concomitant 
medications will be coded using the WHO Drug Dictionary.
Subject Disposition
11.1.4
Subject disposition data will be summarized for all subjects by age group. Number and 
percent of subjects enrolled, subjects who received initial dose of study drug, subjects who 
received adjusted dose of study drug, subjects who completed the study, subjects who 
discontinued treatment, and subjects who discontinued from the study will be tabulated 
together with the reasons for premature discontinuation of study medication and 
discontinuation from study participation by age group.  A listing of all subjects, along with 
data on their disposition, will be provided.
Demographics and Baseline Data
11.1.5
Demographic information and baseline clinical data will be summarized by age group.  
Demographic and baseline characteristics variables will be presented in listings and in 
summary tables.  Medical history, medication history, and screening laboratory tests will be 
presented in listings only.
Baseline will be defined as the most recent measurement prior to the administration of study 
drug, unless otherwise specified.
Study Drug Exposure
11.1.6
Dosing information for each subject will be summarized as descriptive statistics for the total 
amount of study drug received by age group. Also number and percentage of subjects 
receiving initial dose or adjusted dose will be summarized by age group, if relevant. A data 
listing of the dosing information for each subject, including dose interruptions, will also be 
provided.
Secondary Endpoint Analysis
11.1.7
The safety and tolerability of single doses of IV ceftolozane/tazobactam in pediatric patients 
will be evaluated in the Safety population. The safety evaluation will be based on clinical 
review of the following safety parameters:  

Incidence of AEs and SAEs 

AEs and SAEs by relationship to study drug

AEs and SAEs by severity

Deaths

Premature discontinuation from the study due to an AE, regardless of relationship 
to study medication;

Clinical laboratory data; 

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
Vital signs;

Concomitant medications
Adverse Events
11.1.8
All AEs will be coded using MedDRA and displayed in tables and data listings by system 
organ class (SOC) and preferred term (PT). 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined per protocol as any AE with onset after the 
administration of study medication through the end of the study, or any event that was 
present at baseline but worsened in intensity or frequency.  In this study, only treatment-
emergent AEs are captured in the database.
The number and percentage of subjects with the following treatment-emergent adverse event 
categories will be summarized by age group: at least 1 adverse event, AEs by maximum 
severity, AEs by greatest relationship to study drug, at least 1 treatment-related severe AE, at 
least 1 SAE, at least 1 treatment related SAE, at least 1 AE leading to premature treatment 
discontinuation, at least 1 treatment-related AE leading to premature treatment 
discontinuation, at least 1 AE leading to early study withdrawal, at least 1 treatment-related 
AE leading to early study withdrawal, AE leading to death and treatment-related AE leading 
to death.  In addition, summary tables will be provided for all AEs by SOC and PT, AEs by 
severity and AEs by relationship to study drug.  For all summary tables of AE incidences, 
SOC and PTs will be presented in alphabetical order.  
The type and incidence of all AEs and SAEs will be tabulated, and events occurring within 
72 hours of dosing will be analyzed separately. Special attention will be given to local 
tolerability events occurring at time of drug administration and to those patients who 
discontinue due to an adverse event or a serious adverse event. In addition, hypersensitivity 
reactions, events indicative of hemolytic disorders, and events involving Clostridium difficile
will be summarized separately.
In the event of missing data, a conservative approach will be taken.  For example, if the 
relationship of an AE is not recorded in the eCRF the event will be considered to be 
treatment related, or if the severity of the event is missing the event will be considered 
severe. 
All AE summaries will be presented by age group.
No formal hypotheses testing of AE incidence rates will be performed.
All AEs occurring on-study will be listed in subject data listings. 
By-patient AE listings will be provided for the following subsets, as applicable: patient 
deaths; serious adverse events; and adverse events leading to premature study drug 
discontinuation.
Laboratory Data
11.1.9
Clinical laboratory values will be expressed in SI units.

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The actual value and change from baseline study Day 2 will be summarized for each clinical 
laboratory parameter, including hematology and clinical chemistry.  In the event of repeat 
values, the last non-missing value per visit will be used.
All laboratory data will be provided in data listings.  Laboratory results outside the normal 
ranges will be flagged in these listings.
Vital Signs
11.1.10
The actual value and change from baseline to each on-study evaluation (Day 1 and Day 2) 
will be summarized for vital signs. Vital sign measurements will be presented for each 
subject in a data listing. 
Concomitant Medications
11.1.11
Concomitant medications will be coded using the WHO Drug Dictionary.  The use of 
concomitant medications will be included in a by-subject data listing. A separate listing for 
concomitant medications in the mothers of breast-fed patients will also be included. Tabular 
summaries will be presented.
Sample Size and Power Considerations
11.1.12
Thirty-six will participate in this study:  6 subjects are planned in each of the 6 age groups.  
The sample size was chosen based primarily on empirical considerations and feasibility, and 
is considered sufficient to meet the study objectives.
Evaluation Criteria
11.1.13
Safety will be assessed through monitoring adverse events from the start time of study drug 
administration to the end of study.  Any serious adverse events that occur during the study 
will be reported and recorded.
12.0 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The Investigator will be responsible for the accuracy of the data entered in the eCRFs. The 
Investigator will allow designated Sponsor representatives and regulatory bodies to have 
direct access to the source documents to verify the data reported in the eCRFs. Source 
documents are the originals of any documents used by the Investigator or hospital/institution 
that allow verification of the existence of the subject and substantiate the integrity of the data 
collected during the trial (e.g., including, but not limited to, the subject’s medical record). 
Source documents should be available to support all the data recorded in the eCRF, unless 
this is otherwise specified by the Sponsor.
Study Monitoring
12.1
Before an investigational site can enter a patient into the study, a representative of the 
Sponsor will assess the investigational study site to:

Determine the adequacy of the facilities

Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of the Sponsor or its representatives.  

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This will be documented in a Clinical Study Agreement between the Sponsor and the 
investigator.
During the study, a monitor from the Sponsor or representative will have regular contacts 
with the investigational site, for the following:

Provide information and support to the investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed

Perform source data verification.  This includes a comparison of the data in the case 
report forms with the patient’s medical records at the hospital or practice, and other 
records relevant to the study.  This will require direct access to all original records for 
each patient (e.g. clinic charts).

Record and report any protocol deviations not previously sent to the Sponsor.

Confirm AEs and SAEs have been properly documented on CRFs and confirm any 
SAEs have been forwarded to the Sponsor and those SAEs that met criteria for 
reporting have been forwarded to the IRB.
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice.
Protocol Deviations/Amendments
12.1.1
Any deviation from the protocol that has not been approved by the Sponsor and the IRB/EC 
could result in a discontinuation from the study of the center involved. Both the Sponsor and 
the IRB/EC that granted the original approval of the study prior to their implementation 
(unless only logistical or administrative aspects of the trial are involved) must approve any 
amendment(s) to the protocol.
However, in the event of any medical emergency, the Investigator is free to institute any 
medical procedure s/he deems appropriate for proper management of the subject. Such events 
must be promptly reported to the Sponsor and recorded in the source documents.
Discontinuation of the Study
12.1.2
The Sponsor may stop the study at any time on the basis of new information regarding safety 
or efficacy. Additionally, the Sponsor may terminate the study if progress is unsatisfactory.
Audits and Inspections
12.2
Authorized representatives of the Sponsor, a regulatory authority, or an IRB/EC may visit the 
site to perform audits or inspections, including source data verification.  The purpose of a 
Sponsor audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice 
guidelines of the International Conference on Harmonization, and any applicable regulatory 

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requirements.  The Investigator should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection.
Audits for quality assurance of the database may be performed according to relevant 
Standard Operating Procedures at the request of the Sponsor’s Quality Assurance 
department. 
Institutional Review Board
12.3
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB 
approval, and all materials approved by the IRB for this study including the study protocol 
and any amendments, the Informed Consent Form and any other written documents to be 
provided to the subject, and recruitment materials must be maintained by the Investigator and 
made available for inspection.
13.0
QUALITY CONTROL AND QUALITY ASSURANCE
To ensure compliance with Good Clinical Practices and all applicable regulatory 
requirements, the Sponsor may conduct a quality assurance audit. 
14.0
ETHICS
Ethics Review
14.1
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB/EC as appropriate.  The 
investigator must submit written approval to the Sponsor before he or she can enroll any 
patient/subject into the study.
The Investigator is responsible for informing the IRB/EC of any amendment to the protocol 
in accordance with local requirements.  In addition, the IRB/EC must approve all advertising 
used to recruit patients for the study.  The protocol must be re-approved by the IRB/EC upon 
receipt of amendments and annually, in accordance with local regulations.
The Investigator is also responsible for providing the IRB/EC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational 
product.  The Sponsor will provide this information to the Investigator.
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/EC according to local regulations and guidelines.
Ethical Conduct of the Study
14.2
The study will be performed in accordance with the protocol, ethical principles that have their 
origin in the Declaration of Helsinki, and are consistent with International Conference on 
Harmonization (ICH) E6 Good Clinical Practice (GCP): Consolidated Guideline, 21 CFR 
312.120, and any applicable local regulations.
Written Informed Consent
14.3
The Investigator(s) at each center will ensure that the patient (or appropriate legal 
representative) is given full and adequate oral and written information about the nature, 

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purpose, possible risk and benefit of the study.  Patients must also be notified that they are 
free to discontinue from the study at any time.  The patient should be given the opportunity to 
ask questions and allowed time to consider the information provided.
The patient’s (or appropriate legal representative’s) signed and dated informed consent must 
be obtained before conducting any study procedures.
The Investigator(s) must maintain the original, signed Informed Consent Form.  A copy of 
the signed Informed Consent Form must be given to the patient or to the legally acceptable 
representative signing the form and the original retained in the source documents of the study 
participant.
15.0
DATA HANDLING AND RECORDKEEPING
Inspection of Records
15.1
The Sponsor will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, subject charts 
and study source documents, and other records relative to study conduct.
Retention of Records
15.2
The Principal Investigator must maintain all documentation relating to the study for a period 
of 2 years after the last marketing application approval, or if not approved, 2 years following 
the discontinuance of the test article for investigation. If it becomes necessary for the 
Sponsor or health authorities to review any documentation relating to the study, the 
Investigator must permit access to such records.
16.0 PUBLICATION POLICY
The Sponsor may publish the results of company-sponsored studies in a timely manner, 
regardless of whether the outcomes are perceived as positive, neutral, or negative.  
Publications will adhere to external guidelines, including the guidelines adopted by the 
International Society for Medical Publication Professionals and the International Committee 
of Medical Journal Editors, subject to taking appropriate steps to protect the Sponsor’s 
intellectual property rights.  

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17.0
REFERENCES
1. Hayashi T, Yada H, Anai M, Umano T, Kawazu K, Anai S, Kaziwara T, Yamasaki K. 
Single dose toxicity studies of tazobactam/piperacillin and tazobactam. J Toxicol Sci. 
1994a;19 Suppl 2:145-53.
2. Hayashi T, Yada H, Auletta C, Daly I, Knezevich A, Cockrell B. A six-month 
intraperitoneal repeated dose toxicity study of tazobactam/piperacillin and tazobactam 
in rats. J Toxicol Sci. 1994b;19 Suppl 2:155-76.
3. Zosyn [package insert]. Philadelphia, PA: Wyeth Corporation; 2009. 
4. Sato T, Lochry EA, Hoberman AM, Christian MS. Reproductive and developmental 
toxicity studies of tazobactam/piperacillin or tazobactam(1)—Fertility and general 
reproduction study in rats with intraperitoneal administration. J Toxicol Sci. 
1994a;19(suppl 2):199-24.
5. Sato T, Lochry EA, Hoberman AM, Christian MS. Reproductive and developmental 
toxicity studies of tazobactam/piperacillin or tazobactam (3): perinatal and postnatal 
study in rats with intraperitoneal administration. J Toxicol Sci. 1994c;19(suppl 2):233-
47.
6. U.S. Department of Health and Human Services. Food and Drug Administration. 
Guidance for Industry: General Considerations for Pediatric Pharmacokinetic Studies 
for Drugs and Biological Products, November 1998.