Conditions: Complicated Urinary Tract Infection Pyelonephritis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 134
Healthy volunteers: no

Brief summary:
This study aims to evaluate the safety and tolerability of MK-7625A (ceftolozane/tazobactam) compared with that of meropenem in pediatric participants with cUTI, including pyelonephritis.

Detailed description:

Arms:
arm 1: Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose) administered intravenously (IV) every 8 hours for 7-14 days arm 2: Meropenem 20 mg/kg (maximum 1 g/dose) administered IV every 8 hours for 7-14 days

Interventions: intervention 1: Ceftolozane/Tazobactam intervention 2: Meropenem
Intervention descriptions: intervention 1: 12 to \<18 years of age: Ceftolozane 1 g/dose; Tazobactam 0.5 g/dose via a 60-minute (±10 minutes) IV infusion every 8 hours for 7-14 days. \<12 years of age: Ceftolozane 20 mg/kg with Tazobactam 10 mg/kg (not to exceed Ceftolozane 1 g and Tazobactam 0.5 g) via a 60-minute (±10 minutes) IV infusion every 8 hours for 7-14 days. intervention 2: Meropenem 20 mg/kg (maximum 1 g/dose) administered IV every 8 hours for between 7 to 14 days.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03230838 
Document Date: 
14-Sep-2020
A Phase 2, Randomized, Active Comparator-Controlled, Multicenter, 
Double-Blind Clinical Trial to Study the Safety and Efficacy of 
Ceftolozane/Tazobactam (MK-7625A) Versus Meropenem in 
Pediatric Subjects with Complicated Urinary Tract Infection, 
Including Pyelonephritis


Product:  MK-7625A 
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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.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase 2, Randomized, Active Comparator-Controlled, Multicenter, Double-Blind Clinical 
Trial to Study the Safety and Efficacy of Ceftolozane/Tazobactam (MK-7625A) Versus 
Meropenem in Pediatric Subjects with Complicated Urinary Tract Infection, Including 
Pyelonephritis
IND NUMBER:  104,490
EudraCT NUMBER:  2016-004153-32
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 10
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 17
2.0
TRIAL DESIGN........................................................................................................ 18
Trial Design ........................................................................................................... 18
Trial Diagram........................................................................................................ 20
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 20
Primary Objective(s) & Hypothesis(es).............................................................. 20
Secondary Objective(s) & Hypothesis(es)........................................................... 21
Exploratory Objectives......................................................................................... 21
4.0
BACKGROUND & RATIONALE.......................................................................... 21
Background ........................................................................................................... 21
Pharmaceutical and Therapeutic Background .................................................... 21
Ceftolozane/Tazobactam.............................................................................. 21
Complicated Urinary Tract Infection........................................................... 23
Completed Preclinical and Clinical Trials of Ceftolozane/Tazobactam............. 24
Ongoing Clinical Trials of Ceftolozane/Tazobactam ......................................... 25
Information on Other Trial-related Therapy....................................................... 26
Rationale................................................................................................................ 26
Rationale for the Trial and Selected Subject Population .................................... 26
Rationale for Sample Size............................................................................ 27
Rationale for Dose Selection/Regimen............................................................... 28
Rationale for Ceftolozane/Tazobactam Dosage........................................... 28
Rationale for the Use of Comparator........................................................... 32
Rationale for Comparator Dosage ............................................................... 32
Rationale for Duration of Therapy and Optional Oral Step-Down 
Antibiotic Therapy....................................................................................... 33
Rationale for Endpoints ...................................................................................... 33
Rationale for Safety Endpoints.................................................................... 33
 
 
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Rationale for Efficacy Endpoints................................................................. 34
4.2.3.2.1
Clinical Outcome.................................................................................. 35
4.2.3.2.2
Microbiological Outcome..................................................................... 36
Rationale for Pharmacokinetic Endpoints ................................................... 38
Benefit/Risk ........................................................................................................... 38
5.0
METHODOLOGY ................................................................................................... 39
Entry Criteria........................................................................................................ 39
Diagnosis/Condition for Entry into the Trial...................................................... 39
Subject Inclusion Criteria.................................................................................... 39
Subject Exclusion Criteria .................................................................................. 42
Trial Treatment(s) ................................................................................................ 44
Intravenous Trial Treatments.............................................................................. 44
Optional Oral Step-down Therapy...................................................................... 46
Trial Treatments: Administrative Considerations............................................... 47
Dose Selection .................................................................................................... 47
Dose Selection (Preparation) ....................................................................... 47
Timing of Dose Administration.......................................................................... 48
Trial Blinding...................................................................................................... 48
Randomization ...................................................................................................... 48
Stratification.......................................................................................................... 48
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 49
Rescue Medications & Supportive Care............................................................. 49
Diet/Activity/Other Considerations..................................................................... 49
Subject Withdrawal/Discontinuation Criteria................................................... 49
Discontinuation of Treatment ............................................................................. 49
Withdrawal from the Trial .................................................................................. 51
Subject Replacement Strategy............................................................................. 51
Beginning and End of the Trial ........................................................................... 51
Clinical Criteria for Early Trial Termination ................................................... 51
6.0
TRIAL FLOW CHART ........................................................................................... 52
7.0
TRIAL PROCEDURES ........................................................................................... 55
 
 
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Trial Procedures ................................................................................................... 55
Administrative Procedures.................................................................................. 55
Informed Consent/Assent............................................................................. 55
7.1.1.1.1
General Informed Consent/Assent........................................................ 55
Inclusion/Exclusion Criteria ........................................................................ 56
Subject Identification Card .......................................................................... 56
Medical History ........................................................................................... 56
Prior and Concomitant Medications Review............................................... 56
7.1.1.5.1
Prior Medications.................................................................................. 56
7.1.1.5.2
Concomitant Medications..................................................................... 57
Assignment of Screening Number............................................................... 57
Assignment of Treatment/Randomization Number..................................... 57
Trial Compliance (Medication).................................................................... 57
Clinical Procedures/Assessments........................................................................ 57
Body Weight, Height and Vital Signs.......................................................... 57
Physical Examination................................................................................... 58
Assessment of Clinical Signs and Symptoms of Complicated Urinary 
Tract Infection, Including Pyelonephritis.................................................... 58
Adverse Event Monitoring........................................................................... 58
Assessment of Clinical Outcome................................................................. 58
Assessment of Microbiological Outcome.................................................... 59
Assessment of Composite Clinical and Microbiological Outcome............. 59
Assessment of Emergent Infection .............................................................. 59
Laboratory Procedures/Assessments .................................................................. 59
Laboratory Safety Evaluations (Hematology and Chemistry)..................... 59
Urine Microscopy ........................................................................................ 60
Pregnancy Testing........................................................................................ 61
Assessment of Creatinine Clearance............................................................ 61
Urine Samples for Culture ........................................................................... 61
Blood Samples for Culture........................................................................... 62
Pharmacokinetic Evaluations....................................................................... 63
Other Procedures................................................................................................. 63
Withdrawal/Discontinuation........................................................................ 63
 
 
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Lost to Follow-up......................................................................................... 64
Unblinded Pharmacist.................................................................................. 64
Subject Blinding/Unblinding ....................................................................... 64
Calibration of Critical Equipment................................................................ 65
Visit Requirements.............................................................................................. 65
Screening...................................................................................................... 65
Randomization Visit .................................................................................... 65
Clinical Assessment Visits on Intravenous Study Treatment...................... 66
End of IV Treatment Visit ........................................................................... 66
Clinical Assessment Visit on Oral Step-down Therapy .............................. 66
End of Treatment Visit................................................................................. 66
Test of Cure Visit......................................................................................... 67
Last Follow-up Visit .................................................................................... 67
Subjects Who Prematurely Discontinue From Study Treatment or the 
Trial.............................................................................................................. 67
Assessing and Recording Adverse Events .......................................................... 67
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 68
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 68
Immediate Reporting of Adverse Events to the Sponsor.................................... 69
Serious Adverse Events ............................................................................... 69
Events of Clinical Interest............................................................................ 70
Evaluating Adverse Events................................................................................. 70
Sponsor Responsibility for Reporting Adverse Events ...................................... 73
TRIAL GOVERNANCE AND OVERSIGHT................................................... 73
Executive Oversight Committee......................................................................... 73
Data Monitoring Committee............................................................................... 73
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 73
Statistical Analysis Plan Summary ..................................................................... 74
Responsibility for Analyses/In-house Blinding .................................................. 75
Hypotheses/Estimation ......................................................................................... 76
Analysis Endpoints ............................................................................................... 76
Safety Endpoints ................................................................................................. 76
 
 
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Adverse Events ............................................................................................ 76
Laboratory Data ........................................................................................... 76
Vital Signs.................................................................................................... 77
Efficacy Endpoints.............................................................................................. 77
Secondary Efficacy Endpoints..................................................................... 77
Exploratory Efficacy Endpoints................................................................... 77
Pharmacokinetic Endpoints ................................................................................ 78
Analysis Populations............................................................................................. 78
Safety Analysis Populations ............................................................................... 78
Efficacy Analysis Populations ............................................................................ 78
Statistical Methods................................................................................................ 79
Statistical Methods for Safety Analyses ............................................................. 79
Statistical Methods for Efficacy Analyses.......................................................... 81
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 83
Analyses of Baseline Characteristics and Demographics............................ 83
Population Pharmacokinetic Analyses......................................................... 84
Interim Analyses ................................................................................................... 84
Multiplicity ............................................................................................................ 84
Sample Size and Power Calculations .................................................................. 84
Subgroup Analyses ............................................................................................... 85
Compliance (Medication Adherence).................................................................. 85
Extent of Exposure................................................................................................ 86
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 86
Investigational Product ........................................................................................ 86
Packaging and Labeling Information ................................................................. 87
Clinical Supplies Disclosure................................................................................. 88
Storage and Handling Requirements.................................................................. 88
Discard/Destruction/Returns and Reconciliation .............................................. 88
Standard Policies................................................................................................... 88
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 88
Confidentiality....................................................................................................... 88
 
 
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Confidentiality of Data ....................................................................................... 88
Confidentiality of Subject Records..................................................................... 89
Confidentiality of Investigator Information........................................................ 89
Confidentiality of IRB/IEC Information............................................................. 89
Compliance with Financial Disclosure Requirements....................................... 90
Compliance with Law, Audit and Debarment ................................................... 90
Compliance with Trial Registration and Results Posting Requirements ........ 92
Quality Management System............................................................................... 92
Data Management................................................................................................. 92
Publications ........................................................................................................... 93
11.0
LIST OF REFERENCES......................................................................................... 95
12.0
APPENDICES......................................................................................................... 100
Merck Code of Conduct for Clinical Trials...................................................... 100
Approximate Blood Volumes Drawn/Collected by Trial Visit....................... 102
List of Abbreviations and Definitions of Terms............................................... 103
13.0
SIGNATURES......................................................................................................... 106
Sponsor's Representative ................................................................................... 106
Investigator.......................................................................................................... 106
 
 
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LIST OF TABLES
Table 1
Ceftolozane Exposure and Target Attainment Summary for Simulated Adult 
and Pediatric Subjects ............................................................................................ 30
Table 2
Tazobactam Exposure and Target Attainment Summary for Simulated Adult 
and Pediatric Subjects ............................................................................................ 31
Table 3
Clinical Outcome Categories.................................................................................. 36
Table 4
Microbiological Outcome Categories..................................................................... 37
Table 5
Composite Clinical and Microbiological Outcome Categories .............................. 37
Table 6
Emergent Infection Categories ............................................................................... 38
Table 7
Intravenous Trial Treatments.................................................................................. 45
Table 8
Recommended Oral Step-down Therapy Options.................................................. 47
Table 9
Laboratory Safety Evaluations................................................................................ 60
Table 10 Evaluating Adverse Events .................................................................................... 71
Table 11 Efficacy Analysis Populations................................................................................ 79
Table 12 Analysis Strategy for Safety Parameters................................................................ 81
Table 13 Analysis Strategy for Efficacy Variables ............................................................... 82
Table 14 Estimated Two-sided 95% Confidence Intervals Based on Different Assumed 
Observed Rates of Efficacy Endpoints................................................................... 83
Table 15 Estimated Treatment Differences and Two-sided 95% Confidence Intervals ....... 85
Table 16 Product Descriptions .............................................................................................. 87
Table 17 Approximate Blood Volumes Collected by Trial Visit........................................ 102
 
 
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LIST OF FIGURES
Figure 1
Trial Diagram...................................................................................................... 20
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 3
14-SEP-2020
Due to enrollment challenges in the 
remaining age groups in both this trial in 
pediatric subjects with cUTI 
(MK-7625A-034) and also in the 
companion trial in pediatric subjects with 
cIAI (MK-7625A-035), individual study 
age group minimum requirements for 
Groups 3-5 were removed in both studies, 
and the overall combined enrollment 
minimum targets for Groups 3 and 5 were 
also reduced to facilitate more timely 
availability of these important pediatric 
data to health care providers and patients. 
These changes do not impact the key goals 
or scientific validity of either study.
Amendment 2
26-APR-2019
Enrollment targets for Groups 3-5 were 
applied across the present trial in pediatric 
subjects with cUTI (MK-7625A-034) and 
the companion trial in pediatric subjects 
with cIAI (MK-7625A-035).
Amendment 1/Ukraine specific amendment
30-APR-2018
Country-specific amendment to exclude 
enrollment of subjects <3 months old 
(Group 5) in Ukraine.
Original protocol
21-MAR-2017
Not applicable.
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
2.1
4.2.1.1
5.2.1
5.4
Trial Summary
Trial Design
Intravenous Trial Treatments
Subject Inclusion Criteria
Stratification
Removed minimum number of 
at least 4 subjects per study 
(MK-7625A-034 and MK-
7625A-035) in Groups 3, 4, 
and 5.
Reduced minimum enrollment 
targets for Groups 3 and 5 
across both studies.
Due to enrollment challenges 
in the remaining age groups, 
individual study age group 
minimum requirements for 
Groups 3-5 were removed in 
both the MK-7625A-034 and 
MK-7625A-035 studies.  
Additionally, the overall 
combined enrollment 
minimum targets for Groups 3 
and 5 were reduced to facilitate 
more timely availability of 
these important pediatric data
to health care providers and 
patients. These changes do not 
impact the key goals or 
scientific validity of either 
study.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
5.1.2
5.1.3
5.10
6
7.1.1.1
7.1.1.1.1
7.1.1.3
7.1.5.1
7.2
7.2.2
7.2.3.1
7.2.3.2
Trial Summary
Subject Inclusion Criteria
Subject Exclusion Criteria
Beginning and End of the Trial
Trial Flow Chart
Informed Consent/Assent
General Informed 
Consent/Assent
Subject Identification Card
Screening
Assessing and Recording 
Adverse Events
Reporting of Pregnancy and 
Lactation to the Sponsor
Serious Adverse Events
Events of Clinical Interest
Updated text for informed 
consent process
Updated to align with Merck 
standard protocol template
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
10.1.2
Confidentiality of Subject 
Records
4.2.3.2.2
Microbiological Outcome
Removed language that 
emergent infections are 
considered to have an 
unfavorable microbiological 
response.
As microbiological outcome is 
meant to capture the persistence 
or eradication specifically of the 
baseline pathogen, emergent 
infections will not contribute to 
the microbiological outcome. 
This change aligns with other 
studies in the ZERBAXA 
program, wherein emergent 
infections are distinct from the 
overall microbiological 
outcome endpoint and are 
described separately in the 
CSR.
Table 6 “Emergent Infection 
Categories”
Added “and through the TOC 
visit” to the definition of new 
infection. 
To clarify the window in which 
new infections will be recorded. 
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.3 
Subject Exclusion Criteria
For chronic administration of 
systemic corticosteroids that 
could qualify as an 
immunosuppressing condition 
at screening, added the non-
weight-based definition for 
participants weighing >20 kg. 
To align the pediatric-specific 
definition of 
immunosuppression due to 
corticosteroid use with other 
protocols in the ZERBAXA 
program.
5.2.5
6.0
Timing of Dose 
Administration
Trial Flow Chart 
Added text clarifying 
maximum duration of 
antibiotics. 
To clarify that the final day of 
study treatment may extend into 
Day 15 to accommodate 
different start and stop times of 
the IV study treatment and/or 
dosing schedules of the oral 
step-down therapy.
5.8.1
Discontinuation of Treatment 
Added “required for IV study 
treatment only” to 
discontinuation criteria for 
development of moderate or 
severe impairment of renal 
function. 
The lower limit of 
50 mL/min/1.73 m2 only 
applies to 
ceftolozane/tazobactam and not 
to the various optional oral step-
down treatment options.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.10
Beginning and End of the Trial
Text defining the end of the 
trial as the last subject’s last 
visit or contact was changed to 
defining the end of the trial as 
when the last data is available 
in either study, MK-7625A-
034 or MK-7625A-035, 
whichever occurs later.
Updated to reflect the fact that 
the safety data will be combined 
for analysis across the 2 studies, 
thus the final analysis cannot 
begin until both studies are 
completed and final data from 
both trials are available.
7.1.4.4
Subject Blinding/Unblinding
Updated template text to 
describe who may be 
unblinded following 
unblinding.
This revision will allow greater 
flexibility when describing who 
may become unblinded to a 
single participant’s treatment 
following an unblinding and 
allows the principal 
investigator, site personnel, and 
Sponsor personnel to conduct 
appropriate follow-up medical 
care for the participant once an 
emergency unblinding has taken 
place.
8.11
8.12
Compliance (Medication 
Adherence)
Extent of Exposure
Updated the IV study 
treatment and overall study 
treatment (including oral step-
down therapy) compliance 
definition and how exposures 
will be summarized.
It is clinically informative to 
know the compliance and extent 
of exposure for treated subjects.  
In addition, subjects overall 
study treatment exposure is an 
important criterion to evaluate 
the CE analysis population. 
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Global
Global
Minor editorial and document 
formatting revisions.
Minor syntax and grammar 
edits made for clarity and 
correctness.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Ceftolozane/tazobactam (MK-7625A) versus Meropenem in Pediatric 
cUTI
Sponsor Product Identifiers
MK-7625A
Ceftolozane/tazobactam
Trial Phase
2
Clinical Indication
Treatment of complicated urinary tract infection (cUTI), including 
pyelonephritis
Trial Type
Interventional
Type of control
Active control without placebo
Route of administration
Intravenous (IV) with optional oral step-down therapy
Trial Blinding
Double-blind
Treatment Groups
Subjects will be randomized to the experimental 
(ceftolozane/tazobactam) or comparator (meropenem) treatment arm 
to receive IV study treatment administered as a 60-minute (±10 
minutes) infusion as follows:
Group 1 (Ages 12 to <18 years, n≥50 combined with Group 2):
Ceftolozane 1 g and tazobactam 0.5 g IV every 8 hours OR
Meropenem 20 mg/kg (maximum 1 g/dose) IV every 8 hours
Group 2 (Ages 6 to <12 years, n≥50 combined with Group 1):
Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 
ceftolozane 1 g and tazobactam 0.5 g/dose) IV every 8 hours OR
Meropenem 20 mg/kg (maximum 1 g/dose) IV every 8 hours
Group 3 (Ages 2 to <6 years, n≥57 combined with same age group in 
MK-7625A-035):
Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 
ceftolozane 1 g and tazobactam 0.5 g/dose) IV every 8 hours OR
Meropenem 20 mg/kg (maximum 1 g/dose) IV every 8 hours
Group 4 (Ages 3 months to <2 years, n≥24 combined with same age 
group in MK-7625A-035):
Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 
ceftolozane 1 g and tazobactam 0.5 g/dose) IV every 8 hours OR
Meropenem 20 mg/kg (maximum 1 g/dose) IV every 8 hours
Group 5 (Ages birth [>32 weeks gestational age and ≥7 days 
postnatal] to <3 months, n≥21 combined with same age group in MK-
7625A-035):
Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 
ceftolozane 1 g and tazobactam 0.5 g/dose) IV every 8 hours OR
Meropenem 20 mg/kg* (maximum 1 g/dose) IV every 8 hours
*NOTE: Some literature supports a higher meropenem dosage (up to 
30 mg/kg every 8 hours) for subjects 14 days to <3 months of age, 
therefore meropenem dosing up to 30 mg/kg every 8 hours may be 
used for subjects 14 days to <3 months of age at the investigator’s 
discretion.
NOTE: In Ukraine, enrollment will be limited to subjects 3 months to 
< 18 years of age (Groups 1-4). Enrollment of subjects < 3 months of 
age (Group 5) is not applicable at Ukrainian study sites.
 
 
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Number of trial subjects
Approximately 240 (combined across MK-7625A-034 and MK-
7625A-035) subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 3 years
from the time the first subject (or their legally acceptable 
representative) provides documented informed consent/assent until the 
last subject’s last study-related contact
Duration of Participation
Each subject will participate in the trial for approximately 5 to 7 
weeks from the time the subject or subject’s legal representative 
provides documented informed consent  until the last subject’s last 
study-related contact. After a screening phase of up to 48 hours, each 
subject will receive study treatment (IV only or IV + oral) for a 
minimum of 7 to a maximum of 14 days. After the end of treatment, 
each subject enters a follow-up phase consisting of a Test of Cure 
(TOC) Visit 5 to 9 days after the last dose of study treatment and a 
Last Follow-up (LFU) Visit 28 to 35 days after the last dose of study 
treatment.
A list of abbreviations used in this document can be found in Appendix 12.3.
2.0 TRIAL DESIGN
Trial Design
This is a Phase 2 randomized, active comparator-controlled, multicenter, double-blind trial 
evaluating the safety and efficacy of ceftolozane/tazobactam (MK-7625A) versus meropenem 
in pediatric subjects from birth (defined as >32 weeks gestational age and ≥7 days postnatal) 
to <18 years of age with cUTI, including pyelonephritis.
MK-7625A-035 
is 
a 
companion 
Phase 
2
randomized, 
double-blind 
trial 
of 
ceftolozane/tazobactam (plus metronidazole) versus meropenem in pediatric subjects with 
cIAI; MK-7625A-034 and MK-7625A-035 will be pooled together for a combined safety 
database. Thus, approximately 240 subjects (combined across MK-7625A-034 and MK-
7625A-035) will be stratified by age to receive study treatment. After minimum enrollment 
targets for each age group are met (202 subjects total), additional subjects (combined across
MK-7625A-034 and MK-7625A-035) will be enrolled in any of the 5 age groups.
In MK-7625A-034, subjects will be randomized in a 3:1 ratio to receive IV 
ceftolozane/tazobactam or meropenem. After receiving at least 9 doses of double-blind IV 
study treatment, subjects in either treatment arm may be switched to open-label, standard-of-
care oral step-down antibiotic therapy at the investigator’s discretion. Oral step-down therapy 
is considered study treatment. Recommendations for oral step-down therapy are provided in 
Section 5.2.2 – Optional Oral Step-down Therapy.
The total duration of study treatment (IV only or IV + oral) is a minimum of 7 days and a 
maximum of 14 days.
Randomization Ratio
3:1 for ceftolozane/tazobactam: meropenem.
 
 
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Subjects will be randomized to the experimental (ceftolozane/tazobactam) or comparator 
(meropenem) treatment arm to receive IV study treatment administered as a 60-minute 
(±10 minutes) infusion as follows:
Group 1 (Ages 12 to <18 years, n≥50 combined with Group 2):
Ceftolozane 1 g and tazobactam 0.5 g IV every 8 hours OR
Meropenem 20 mg/kg (maximum of 1 g/dose) IV every 8 hours
Group 2 (Ages 6 to <12 years, n≥50 combined with Group 1):
Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum ceftolozane 1 g and tazobactam
0.5 g/dose) IV every 8 hours OR
Meropenem 20 mg/kg (maximum of 1 g/dose) IV every 8 hours
Group 3 (Ages 2 to <6 years, n≥57 combined with same age group in MK-7625A-035):
Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum ceftolozane 1 g and tazobactam
0.5 g/dose) IV every 8 hours OR
Meropenem 20 mg/kg (maximum of 1 g/dose) IV every 8 hours
Group 4 (Ages 3 months to <2 years, n≥24 combined with same age group in MK-7625A-035):
Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum ceftolozane 1 g and tazobactam
0.5 g/dose) IV every 8 hours OR
Meropenem 20 mg/kg (maximum of 1 g/dose) IV every 8 hours
Group 5 (Ages birth [>32 weeks gestational age and ≥7 days postnatal] to <3 months, 
n≥21 combined with same age group in MK-7625A-035):
Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum ceftolozane 1 g and tazobactam
0.5 g /dose) IV every 8 hours OR
Meropenem 20 mg/kg* (maximum of 1 g/dose) IV every 8 hours
*NOTE: There is literature that supports a higher meropenem dosage (up to 30 mg/kg every 8 
hours) for subjects 14 days to <3 months of age. Therefore, meropenem dosing up to 30 mg/kg 
every 8 hours may be used for subjects 14 days to <3 months of age at the investigator’s 
discretion.
NOTE: In Ukraine, enrollment will be limited to subjects 3 months to < 18 years of age (Groups 
1-4). Enrollment of subjects < 3 months of age (Group 5) is not applicable at Ukrainian study 
sites. 
Clinical and microbiological assessments will be performed at the following visits:

End of IV Treatment Visit (EOIV)

End of Treatment Visit (EOT)

Test of Cure Visit (TOC)
NOTE: For subjects who receive IV study treatment only (without optional oral step-down 
therapy), a separate assessment does not need to be performed at the EOT Visit; the EOIV 
Visit will serve as the EOT Visit.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
 
 
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Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Trial Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
In male and female subjects from birth (>32 weeks gestational age and ≥7 days postnatal) to 
<18 years of age with cUTI:
Primary Objective(s) & Hypothesis(es)
To evaluate the safety and tolerability of ceftolozane/tazobactam compared with that of 
meropenem
 
 
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Secondary Objective(s) & Hypothesis(es)
1.
To evaluate the efficacy of ceftolozane/tazobactam compared with that of meropenem 
with respect to clinical response at the EOT and TOC Visits
2.
To evaluate the efficacy of ceftolozane/tazobactam compared with that of meropenem 
with respect to per-subject microbiological response at the EOT and TOC Visits
Exploratory Objectives
1.
To evaluate the pharmacokinetics (PK) of ceftolozane and tazobactam
2.
To evaluate the efficacy of ceftolozane/tazobactam compared with that of meropenem 
with respect to clinical response at the EOIV Visit
3.
To evaluate the efficacy of ceftolozane/tazobactam compared with that of meropenem 
with respect to per-subject microbiological response at the EOIV Visit
4.
To evaluate the efficacy of ceftolozane/tazobactam compared with that of meropenem 
with respect to per-pathogen microbiological response at the EOIV, EOT, and TOC 
Visits
5.
To evaluate the efficacy of ceftolozane/tazobactam compared with that of meropenem 
with respect to composite response (clinical response and per-subject microbiological 
response) at the EOIV, EOT, and TOC Visits
NOTE: For subjects who receive IV study treatment only (without optional oral step-down 
therapy), a separate assessment does not need to be performed at the EOT Visit; the EOIV 
Visit will serve as the EOT Visit.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on ceftolozane/tazobactam.
Pharmaceutical and Therapeutic Background
Ceftolozane/Tazobactam
Ceftolozane/tazobactam, a novel combination of ceftolozane and the β-lactamase inhibitor 
(BLI), tazobactam, is used to treat serious bacterial infections. Ceftolozane is a member of the 
cephalosporin class of antibiotics, which is well characterized in terms of safety, efficacy, and 
general antimicrobial profile. While ceftolozane alone represents an important therapeutic 
option for the treatment of infections caused by Pseudomonas aeruginosa, the efficacy of 
ceftolozane for the treatment of suspected gram-negative infections in general could be 
compromised by the spread of extended-spectrum β-lactamase (ESBL)-producing bacteria. 
Combining ceftolozane with a BLI such as tazobactam broadens its in vitro spectrum of 
 
 
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activity to include many drug-resistant Enterobacteriaceae and is thereby likely to improve its 
clinical utility against gram-negative bacteria.
Ceftolozane (both alone and in combination with tazobactam) exhibits time-dependent killing 
activity against various gram-negative organisms, including drug-resistant P. aeruginosa. 
Ceftolozane/tazobactam has been shown to be active against strains of P. aeruginosa that are 
resistant to carbapenems, cephalosporins, fluoroquinolones, and/or aminoglycosides, 
including the majority of multidrug-resistant (MDR) isolates. The in vitro activity of 
ceftolozane/tazobactam against the majority of ESBL-producing gram-negative bacilli and 
important anaerobic pathogens such as Bacteroides fragilis is greater than that of ceftolozane 
alone. Ceftolozane/tazobactam has no activity against enterococci and staphylococci.
Compared with other cephalosporins, ceftolozane requires a lower percentage of time above 
the minimum inhibitory concentration (T>MIC) of 8 µg/mL to achieve bacteriostasis (21% to 
29%) or 1-log killing (27% to 35%) in animal models. Additionally, ceftolozane/tazobactam 
was superior to piperacillin/tazobactam against ESBL-producing Escherichia coli in a mouse 
sepsis model.
Clinical trials in adults have demonstrated that the PK of ceftolozane/tazobactam is linear 
across a wide range of doses (up to 4.5 g [3 g ceftolozane/1.5 g tazobactam] as a single-dose), 
distributes primarily to the extracellular fluid, has a relatively short terminal elimination half-
life (approximately 2 to 3 hours for ceftolozane and 1 hour for tazobactam), and has low 
protein-binding (approximately 16% to 21% for ceftolozane and 30% for tazobactam). In 
adults, at the approved dose of 1.5 g, the mean (coefficient of variation [%CV]) values for area 
under the concentration-time curve (AUC) on Day 1 were 172 (14) and 24.4 (18) µg•h/mL for 
ceftolozane and tazobactam, respectively. The mean (%CV) values for maximum observed 
concentration (Cmax) on Day 1 were 69.1 (11) and 18.4 (16) µg/mL for ceftolozane and 
tazobactam, respectively. As ceftolozane/tazobactam is primarily removed from the systemic 
circulation by renal excretion, dose adjustments are necessary in some subjects with renal 
impairment.
The safety and efficacy of ceftolozane/tazobactam was demonstrated in Phase 3 trials in adult 
subjects with cUTI or complicated intra-abdominal infection (cIAI). In these Phase 3 trials, the 
overall incidence of treatment-emergent adverse events (TEAEs) was similar in the 
ceftolozane/tazobactam and comparator treatment arms. Ceftolozane/tazobactam was found to 
be noninferior to the comparator in these Phase 3 trials.
In summary, ceftolozane is a novel cephalosporin antibiotic that, in combination with a potent 
BLI, tazobactam, has broad-spectrum antibacterial coverage against Enterobacteriaceae, 
including ESBL-producing strains, and MDR P. aeruginosa. Ceftolozane/tazobactam is 
approved for use in adult patients with cUTI, including pyelonephritis, and cIAI (in 
combination with metronidazole) at a dose of 1.5 g (1 g ceftolozane/0.5 g tazobactam) every 
8 hours. Both in vitro and in vivo safety and efficacy data support its continued clinical 
investigation in the pediatric population.
 
 
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Complicated Urinary Tract Infection
In community and hospital settings, urinary tract infections (UTIs) are among the most 
common infections encountered in pediatric patients [1] [2] [3]. Urinary tract infection is 
defined as microorganism colonization in the normally sterile urinary tract (bacteriuria) in the 
presence of urinary symptoms [4]. The frequency of bacteriuria is highest in young children 
and elderly men and women; however, symptomatic infection occurs most frequently in 
females 15 to 29 years of age [4]. The incidence of UTI in the pediatric population is reported 
to be highest overall in the first year of life; the incidence decreases substantially in boys after 
infancy, but increases in girls as they get older [5] [6].
Classification of UTI is performed according to the anatomical site of infection, and 
distinguishes between lower tract infections of the bladder (cystitis) or urethra (urethritis) and 
upper tract infections of the ureter, collecting system, and renal parenchyma (pyelonephritis) 
[7]. Further classification subdivides the condition into uncomplicated UTI and cUTI. 
Complicated UTI that does not involve the upper urinary tract is often referred to as 
complicated lower UTI (cLUTI). Complicated UTI is characterized by white blood cells in the 
urine (pyuria) and a documented microbial pathogen on culture of urine or blood, accompanied 
by local and systemic signs and symptoms, including fever, chills, malaise, flank pain, back 
pain, and/or costovertebral angle (CVA) pain or tenderness, that occur in the presence of a 
functional or anatomical abnormality of the urinary tract or in the presence of catheterization 
[8]. Diagnosis of cUTI is therefore made irrespective of the severity or location of the infection.
As a result of predisposing anatomical or functional abnormalities of the urinary tract, cUTI is 
associated with a higher risk of recurrent infection and relapse in comparison to uncomplicated 
UTI [7] [9]. Conditions that increase the risk of cUTI include the presence of an indwelling 
urinary catheter, increased residual urine after voiding (eg, neurogenic bladder), obstructive 
uropathies such as nephrolithiasis or fibrosis, azotemia caused by intrinsic renal disease, and 
urinary retention, including retention caused by benign prostatic hypertrophy [8]. In the 
pediatric population, the nature of the UTI is presumed complicated when confirmed in 
neonates and infants, owing to the high correlation between functional or anatomical 
abnormalities of the urinary tract and concurrent bacteremia, which ultimately leads to higher 
risk of renal scarring and long-term morbidity in this population [10] [11].
In the pediatric population, obstruction and urinary tract dysfunction are among the most 
frequent causes of UTI [2]. Vesicouretic reflux is the most common obstructive anomaly 
detected in pediatric patients being investigated with their first UTI [12]. Other circumstances 
that affect UTI risk in pediatric patients include lack of circumcision in males, non-retractable 
foreskin (phimosis), labial adhesions, sexual activity, chronic constipation, systemic disorders
(eg, immunological compromise, diabetes mellitus, sickle cell anemia), dysfunctional voiding, 
neuropathic bladder, and other congenital urinary tract abnormalities such as urethral valves, 
pelvi-ureteric junction obstruction, and non-obstructive urinary stasis (eg, prune belly 
syndrome) [1] [2] [13].
Symptoms commonly associated with UTI in adults, such as dysuria, frequency, hesitancy, 
and flank plain, are unreliable in pediatric patients younger than 2 years of age. Urinary tract 
infection complaints in this age group are often nonspecific and may include fever, irritability, 
 
 
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lethargy, poor feeding, gastrointestinal distress, and incontinence; fever represents the most 
common presentation in young pediatric patients [5] [6]. Pediatric patients older than 2 years 
of age tend to exhibit more specific symptoms in accordance with adult UTI, and may present 
with or without fever [2]. The clinical presentation of cUTI may range from simple catheter-
associated UTI to severe obstructive acute pyelonephritis with imminent urosepsis [2]. The 
nonspecific presentation of cUTI together with the high prevalence of UTI in the pediatric 
population dictate a high index of suspicion for UTI in pediatric patients presenting with 
nonspecific symptoms of infection [14].
Urinary tract infections in pediatric patients are associated with significantly higher morbidity 
and more severe long-term sequelae, including impaired renal function and progression to end-
stage renal disease, in comparison to UTIs in adult patients [15]. Furthermore, UTIs in 
prepubertal girls have been linked to potential complications in subsequent pregnancy [15]. 
Renal scarring represents the most significant difference in disease pathophysiology between 
the adult and pediatric populations; pediatric patients younger than 2 years of age are more 
likely to be predisposed to damage, given their developmental stage. Sequelae associated with 
renal scarring can include hypertension, proteinuria, renal damage, and chronic renal failure, 
which may necessitate dialysis treatment in adulthood [16].
Across all pediatric age groups, E. coli is the most common cause of UTI, followed by 
Klebsiella spp., Proteus mirabilis, other Enterobacteriaceae, Enterococcus spp., P. aeruginosa, 
and Staphylococcus saprophyticus [17] [18]. Uncomplicated UTIs are most commonly caused 
by E. coli, whereas a broader range of microorganisms may be responsible for cUTIs [7] [19]. 
Furthermore, cUTIs are associated with an increased likelihood of drug resistance in the 
infecting microorganisms, which can further complicate treatment and lead to high mortality 
rates [7]. Drug resistance in pediatric patients with cUTI is attributed to recurrent infection, 
instrumentation, and exposure to multiple courses of antibiotics [7].
Empiric antimicrobial therapy for cUTI should be sufficiently broad spectrum to cover the 
most commonly isolated pathogens. Treatment should be individualized for the subject, based 
on subject tolerance, clinical presentation, prior antimicrobial use and urine culture reports, 
and known or suspected institutional susceptibilities [5] [20].
Completed Preclinical and Clinical Trials of Ceftolozane/Tazobactam
Refer to the IB/approved labeling for detailed information on preclinical and completed 
clinical trials of ceftolozane/tazobactam.
The primary data supporting the efficacy of ceftolozane/tazobactam in the cUTI indication was 
derived from 2 large, identical, global, multicenter, randomized, double-blind, active-
controlled Phase 3 trials (CXA-cUTI-10-04 [MK-7625A-004] and CXA-cUTI-10-05 [MK-
7625A-005]). In both trials, adult subjects were randomized 1:1 to receive either 
ceftolozane/tazobactam 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) IV every 8 hours or 
levofloxacin IV once daily administered for 4 to 14 days. The results indicated that 
ceftolozane/tazobactam was noninferior to levofloxacin in the treatment of cUTI in adults [21].
 
 
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In the treatment of adult subjects with nosocomial pneumonia (NP) (MK-7625A-008), 
ceftolozane/tazobactam 3 g (2 g ceftolozane and 1 g tazobactam) IV every 8 hours 
demonstrated noninferiority compared with meropenem 1 g IV every 8 hours for FDA and 
EMA primary and key secondary efficacy endpoints. Overall, both treatment groups 
demonstrated comparable per-pathogen clinical cure and microbiological eradication rates at 
the TOC visit against commonly isolated pathogens, including P. aeruginosa, 
Enterobacteriaceae, and Haemophilus influenzae.
The pediatric development program for ceftolozane/tazobactam included a pediatric PK and 
safety trial of ceftolozane/tazobactam, CXA-PEDS-13-08 (MK-7625A-010) [22]. This was a 
Phase 1, multicenter, single-dose, noncomparative, open-label trial in pediatric subjects with 
proven or suspected gram-negative infection or for peri-operative prophylaxis. This study had 
6 age-based cohorts and enrolled a total of 43 subjects; 37 (86.0%) received study drug. Dose
selections of ceftolozane/tazobactam for each 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: 32 weeks gestation, 7 days postnatal to 3 months, and Group 6: 32 weeks 
gestation, 7 days postnatal to 3 months) were projected to achieve exposures similar to those 
observed in adults who received the approved dose for cUTI and cIAI. Ceftolozane and 
tazobactam PK parameters were generally comparable across Groups 1 to 4 (ages 3 months to 
<18 years). Subjects in Groups 5 and 6 (birth [7 days postnatal] to <3 months of age) had a 
lower CL than older children; however, there was no consistent trend in the weight-normalized 
CL across Groups 1 to 6. Data from MK-7625A-010 were used to determine appropriate doses 
for the present trial, as detailed in Section 4.2.2.1 – Rationale for Ceftolozane/Tazobactam 
Dosage.
Ceftolozane/tazobactam administered as a single, age-based dose was generally well tolerated
in MK-7625A-010. Overall, 11 subjects (29.7%) experienced a total of 26 TEAEs.  No severe 
TEAEs or TEAEs leading to discontinuation of study treatment were reported, and there were 
no deaths during the trial. Two subjects had nonserious treatment-related TEAEs (1 subject in 
Group 1 with dizziness and 1 subject in Group 3 [30/15 mg/kg dose] with bradycardia and 
tachycardia). Three subjects had SAEs (1 subject from Group 1 with pneumonia, 1 subject 
from Group 2 with infective pulmonary exacerbation of cystic fibrosis, and 1 subject from 
Group 4 [30/15 mg/kg dose] with device-related sepsis), which were all deemed unrelated to 
trial treatment. No subject in Groups 5 or 6 experienced a treatment-related TEAE or SAE. No 
clinically significant laboratory abnormalities or changes in electrocardiograms were observed 
after administration of ceftolozane/tazobactam.
Ongoing Clinical Trials of Ceftolozane/Tazobactam
Refer to the IB for detailed information for ongoing clinical trials of ceftolozane/tazobactam.  
In addition to the present trial, the current clinical development program for 
ceftolozane/tazobactam includes 4 ongoing/planned clinical studies: 1) a Phase 3, randomized, 
double-blind, active comparator-controlled study comparing ceftolozane/tazobactam plus 
metronidazole versus meropenem in adult Chinese subjects with cIAI, 2) a Phase 2, 
randomized, 
double-blind, 
active 
comparator-controlled 
study 
comparing 
ceftolozane/tazobactam plus metronidazole versus meropenem in pediatric subjects with cIAI, 
 
 
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3) a Phase 1, open-label, noncomparative study evaluating the safety, tolerability, and PK of 
ceftolozane/tazobactam in pediatric subjects with NP, and 4) a Phase 1, non-randomized, 
single-arm, single-site, fixed-sequence open-label, PK, safety, and tolerability study of 
ceftolozane/tazobactam in healthy Chinese subjects.
Information on Other Trial-related Therapy
Subjects in the comparator arm of the present trial (MK-7625A-034) will receive IV 
meropenem (Table 7). Meropenem is a carbapenem antibiotic and is approved for treatment of 
cUTI in pediatric (3 months of age and older) and adult patients [23]. There is no evidence of 
increased risk for any adverse drug reaction in pediatric patients based on the limited available 
data. See Section 4.2.2.2 – Rationale for the Use of Comparator and 4.2.2.3 – Rationale for 
Comparator Dosage for additional details on the efficacy and safety of meropenem in the 
treatment of cUTI.
Meropenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in gram-
positive and gram-negative bacteria through binding to penicillin-binding proteins. Like other 
β-lactam antibiotics, the T>MIC for meropenem has been shown to best correlate with efficacy. 
In preclinical models, meropenem demonstrated activity when plasma concentrations 
exceeded the MIC of the infecting organisms for approximately 40% of the dosing interval.
Rationale
Rationale for the Trial and Selected Subject Population
As described in Section 4.1.1.2 – Complicated Urinary Tract Infection, UTIs are among the 
most common infections encountered in pediatric patients and are associated with an increased 
likelihood of drug resistance, a higher risk of recurrence and relapse, and higher morbidity and 
more severe long-term sequelae than in adult patients. Hence, there is a medical need to 
investigate the use of newer antibacterial agents, such as ceftolozane/tazobactam, in the 
pediatric population.
Ceftolozane/tazobactam has activity against the most commonly encountered pathogens 
associated with pediatric cUTIs and may be a valuable treatment option empirically and for 
the treatment of ESBL-producing Enterobacteriaceae and MDR P. aeruginosa. While
ceftolozane/tazobactam has been demonstrated to be safe and effective in the treatment of 
cUTIs in adults, the safety and efficacy of ceftolozane/tazobactam have not been established 
in pediatric subjects with cUTI. Therefore, the study of ceftolozane/tazobactam in pediatric 
subjects with cUTI is warranted.
Clinical trials have indicated that ceftolozane is well tolerated and generally safe in healthy 
adult subjects, adult subjects with varying degrees of renal impairment, and adult subjects with 
cUTI or cIAI. The Phase 1 PK and safety trial in pediatric subjects (CXA-PEDS-13-08 
[MK-7625A-010]; see Section 4.1.2 – Completed Preclinical and Clinical Trials of 
Ceftolozane/Tazobactam employed an adaptive trial design wherein enrollment of Groups 1 to 
4 (ages 3 months to <18 years) was conducted in parallel but enrollment of Groups 5 and 6 
(ages birth to <3 months) did not begin until PK assessments and subject safety data from the 
 
 
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older age groups were reviewed. Data from this trial revealed that ceftolozane/tazobactam 
doses resulting in exposures similar to those observed in adult subjects with cUTI or cIAI were 
safe and well tolerated in pediatric subjects.
The present trial (MK-7625A-034) will enroll pediatric subjects from birth to <18 years of age
(from 3 months to < 18 years of age in Ukraine) who present with cUTI, including 
pyelonephritis, to establish the safety and efficacy of ceftolozane/tazobactam in this 
population. The pediatric dosing recommendations (see Section 4.2.2.1 - Rationale for 
Ceftolozane/Tazobactam Dosage for rationale for dose selection) were developed using data 
from subjects from birth (>32 weeks gestational age and ≥7 days postnatal) to <18 years of 
age; no data were available from subjects ≤32 weeks gestational age or <7 days postnatal to 3 
months of age. Neonatal renal function is closely related to both gestational age and postnatal 
age. Because serum creatinine fluctuates in the first week of life, the revised Schwartz equation
[24], which will be used to calculate renal function in this population, is not recommended for 
use until after the first week of life. Therefore, the present trial defines “birth” as >32 weeks 
gestational age and ≥7 days postnatal.
Because ceftolozane/tazobactam was well tolerated in the Phase 1 pediatric PK and safety trial
(CXA-PEDS-13-08 [MK-7625A-010]), parallel enrollment into active and comparator groups 
is considered appropriate for the present trial. Investigators, Sponsors, trial personnel, and 
subjects will all be blinded to prevent bias in treatment allocation and in the assessment of 
safety and efficacy. Likewise, randomization will be used to produce similar treatment arms
and reduce bias.
Rationale for Sample Size
This trial is being conducted to establish the safety and tolerability of ceftolozane/tazobactam 
in pediatric subjects with cUTI. The efficacy of ceftolozane/tazobactam in pediatric subjects
with cUTI may be extrapolated from the corresponding adult trials. Therefore, the calculation 
of cumulative sample size for this trial is based on obtaining sufficient data to evaluate the
safety of this drug in pediatric subjects by combining safety data from the present trial and 
MK-7625A-035 (the companion trial in pediatric subjects with cIAI) (see Section 8.9—Sample 
Size and Power Calculations). Combining subjects across both studies is intended to provide 
flexibility and enable timely enrollment of the trials. This is an exploratory trial and is not 
powered to test formal hypotheses.
Approximately 240 subjects (combined across MK-7625A-034 and MK-7625A-035) will 
receive study treatment
(approximately 180 ceftolozane/tazobactam-treated and 60 
comparator-treated subjects). After the minimum enrollment targets for each age group are met
(202 subjects total), additional subjects (combined across MK-7625A-034 and MK-7625A-
035) will be enrolled in any of the 5 age groups.
 
 
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Rationale for Dose Selection/Regimen
Rationale for Ceftolozane/Tazobactam Dosage
The proposed ceftolozane/tazobactam pediatric doses were projected using a population PK 
approach using data from 13 clinical studies (12 adult studies and 1 pediatric study). The PK 
analysis showed that 2-compartment models best described the concentration-time profiles of 
ceftolozane and tazobactam. The fit of the models was improved by including allometric 
scaling using body weight as a covariate on clearance (CL), central volume of distribution 
(Vc), peripheral volume of distribution (Vp), and intercompartmental clearance (Q, for 
tazobactam only). In the final models, renal function (estimated glomerular filtration rate 
[eGFR]) was included as a covariate on CL for ceftolozane. For tazobactam, presence of 
infection (as a categorical variable: Presence or absence) was also a significant covariate on 
CL for tazobactam. Tazobactam CL for subjects was estimated to be 67.7% of the CL for those 
without infection. Infection status did not appear to be a significant covariate on the PK of 
ceftolozane.
The final PK models for ceftolozane and tazobactam were used to simulate the AUC from 0 to 
8 hours (AUC0-8) and the Cmax in pediatric subjects with infections on Day 3, which was shown 
to provide steady-state exposures. To provide a benchmark for evaluating the safety of 
ceftolozane and tazobactam in simulated pediatric subjects, Day 3 plasma exposure parameters 
for adult subjects were simulated. For predicting efficacy of the doses, probability of target 
attainment (PTA) after the first dose for adult subjects and 5 pediatric age groups was also 
simulated.
The criteria used in evaluating the appropriateness of doses were:

The 95th percentile of pediatric ceftolozane and tazobactam exposures (AUC and 
Cmax) on Day 3 not exceeding the corresponding 95th percentile of adult exposures; 
and 

The ceftolozane Day 1 PTA (initial dose) ≥90% based on concentrations exceeding 
an MIC of 4 µg/mL (the Clinical and Laboratory Standards Institute [CLSI]
breakpoint) for at least 30% of the dosing interval and a tazobactam Day 1 PTA 
≥90% based on concentrations exceeding a threshold concentration of 1 µg/mL for at 
least 20% of the dosing interval.
Similar to other β-lactams, the PK target that best correlates with in vivo efficacy for 
ceftolozane is the percentage of the dosing interval during which the free concentration of 
ceftolozane in plasma exceeds the MIC (% fT>MIC). A % fT>MIC of 30% was selected as the 
criterion because data from a neutropenic mouse thigh infection model showed that the 
% fT>MIC ranged from 26.7% to 35.3% for a 1-log kill [25]. The CLSI breakpoints are 
2 µg/mL for Enterobacteriaceae and 4 µg/mL for Pseudomonas aeruginosa. The higher 
breakpoint of 4 µg/mL was chosen to ensure coverage for both organisms.
Because tazobactam does not have intrinsic antibacterial activity, an MIC cannot be 
determined. Instead, the threshold drug concentration (Ct) needed to effectively neutralize the 
β-lactamase enzyme produced by bacteria is used for target attainment [26]. Time above a Ct
 
 
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of 1 µg/mL for free tazobactam exposures of 20%, which is supported by data from a mouse 
model and clinical studies, was used.
Based on the exposure and PTA criteria described above, the simulations in pediatric subjects 
indicated that the following doses are appropriate for evaluation in this trial:

12 to <18 years of age: Ceftolozane 1 g with tazobactam 0.5 g via a 60-minute (±10 
minutes) IV infusion every 8 hours

<12 years of age: Ceftolozane 20 mg/kg with tazobactam 10 mg/kg via a 60-minute 
(±10 minutes) IV infusion every 8 hours (not to exceed a dose of ceftolozane 1 g and 
tazobactam 0.5 g)
The ceftolozane and tazobactam exposures and PTA for adult and pediatric subjects at these 
doses are summarized in Table 1 and Table 2, respectively. As shown in these tables, the 
selected doses provide exposures for the age groups that do not exceed the corresponding 95th 
percentile of adult exposures and achieve PTAs ≥90%.
 
 
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Table 1
Ceftolozane Exposure and Target Attainment Summary for Simulated Adult and Pediatric Subjects
Parameter
Statistic
Adult Subjects 
(n=1000)
Pediatric Age Groupa
1
1000 mg 
(n=1200)
2 
20 mg/kg 
(n=1000)
3 
20 mg/kg 
(n=1000)
4 
20 mg/kg 
(n=1000)
5 
20 mg/kg 
(n=1200)
Age (years)
Mean (SD)
53.57 (19.09)
15.00 (1.74)
9.52 (1.45)
4.51 (1.45)
0.80 (0.44)
0.13 (0.07)
Median
56.00
14.99
9.53
4.53
0.71
0.12
5th, 95th
22.0, 81.0
12.3, 17.7
7.3, 11.8
2.2, 6.7
0.3, 1.7
0.0, 0.2
AUC0-8
(μg h/mL), Day 3
Mean (SD)
213.36 (171.91)
172.11 (78.76)
176.08 (69.92)
153.13 (60.32)
162.04 (63.15)
157.36 (65.19)
Median
176.00
160.00
161.00
141.00
149.00
147.00
5th, 95th
95.3, 388.0
73.2, 319.0
90.3, 315.0
77.0, 268.0
81.2, 276.5
71.3, 282.5
Cmax (μg/mL), Day 3
Mean (SD)
69.66 (45.09)
86.04 (36.25)
92.68 (29.84)
82.37 (23.96)
74.37 (19.33)
62.06 (15.18)
Median
56.10
80.35
86.90
79.35
72.40
60.15
5th, 95th
32.9, 154.0
37.8, 154.0
53.1, 150.0
47.8, 125.0
45.9, 109.0
39.9, 89.4
Target attainmentb
Day 1
N (%)
1000 (100.0)
1188 (99.0)
995 (99.5)
992 (99.2)
1000 (100.0)
1196 (99.7)
5th, 95th = 5th, 95th percentiles; AUC0-8 = area under the concentration-time curve from time of drug administration (time 0) to 8 hours; Cmax = maximum 
observed concentration; h = hours; N = number of subjects achieving target attainment; n = number of subjects; SD = standard deviation
a
Age Group 1, 12 years age <18 years; Age Group 2, 7 years age < 12 years; Age Group 3, 2 years age <7 years; Age 
Group 4, 3 months age <2 years; Age Group 5, 7 days postnatal age <3 months.
b
For ceftolozane, minimum effective concentration is 4 μg/mL and target is attainment of this concentration for 30% of the 8-hour dosing interval.
 
 
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Table 2
Tazobactam Exposure and Target Attainment Summary for Simulated Adult and Pediatric Subjects
Parameter
Statistic
Adult 
Subjects 
(n=
1000)
Pediatric Age Groupa
1 
500 mg
(n=1200)
2 
10 mg/kg
(n=1000)
3
10 mg/kg
(n=1000)
4 
10 mg/kg
(n=1000)
5 
10 mg/kg
(n=1200)
Age (years)
Mean (SD)
46.37 (18.72)
15.00 (1.74)
9.52 (1.45)
4.51 (1.45)
0.80 (0.44)
0.13 (0.07)
Median
44.00
14.99
9.53
4.53
0.71
0.12
5th, 95th
20.0, 78.0
12.3, 17.7
7.3, 11.8
2.2, 6.7
0.3, 1.7
0.0, 0.2
AUC0-8 
(μg h/mL), Day 3
Mean (SD)
80.71 
(148.87)
37.12 (23.29)
38.02 (24.49)
30.22 (19.18)
29.87 (19.05)
26.77 (16.50)
Median
29.80
31.20
32.30
26.10
25.00
22.30
5th, 95th
15.4, 379.0
12.4, 83.1
12.3, 84.5
10.2, 62.9
10.0, 63.5
8.4, 57.3
Cmax (μg/mL), Day 
3
Mean (SD)
30.30 (34.73)
27.92 (14.51)
29.19 (14.69)
24.04 (11.78)
21.69 (10.54)
18.37 (8.81)
Median
17.70
24.75
26.45
21.80
19.50
16.80
5th, 95th
10.3, 108.0
10.7, 54.6
11.7, 57.7
9.6, 46.1
8.5, 42.2
7.6, 35.2
Target attainmentb
Day 1
N (%)
1000 (100.0)
1169 (97.4)
978 (97.8)
950 (95.0)
958 (95.8)
1116 (93.0)
5th, 95th = 5th, 95th percentiles; AUC0-8, area under the concentration-time curve from time of drug administration (time 0) to 8 hours; Cmax, maximum 
observed concentration; N, number of subjects achieving target attainment; n, number of subjects; SD, standard deviation
a
Age Group 1, 12 years age <18 years; Age Group 2, 7 years age < 12 years; Age Group 3, 2 years age <7 years; Age 
Group 4, 3 months age <2 years; Age Group 5, 7 days postnatal age <3 months.
b
For tazobactam, threshold concentration is 1 μg/mL and target is attainment of this concentration for 20% of the 8-hour dosing interval.
 
 
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Varying age-appropriate volumes of a fixed concentration of ceftolozane/tazobactam will be 
administered IV to achieve the intended dose in each pediatric subject. The same IV 
formulation will be used across all age groups.
Rationale for the Use of Comparator
The comparator medication, meropenem, was selected because it is approved in the European 
Union (EU) for the treatment of pediatric patients in this indication and based on its clinical 
utility and safety profile in patients with cUTI [23].
A consensus does not exist for standard of care treatment of cUTI in the pediatric population. 
However, the carbapenem class of antibiotics, including meropenem, is a reliable treatment 
option for cUTI in adults [2]. Meropenem monotherapy has been studied and used extensively 
in the treatment of cUTI in adults, and is recommended in the evidence-based guidelines for 
adults developed by an expert panel as an option for cUTI [2] [23] [27] [28] [29] [30]. 
Meropenem and other carbapenems have also been shown to be safe and effective in the 
treatment of UTIs in pediatric patients [31] [32] [33] [34] [35] [36] [37] [38] [39]. The safety 
profile of meropenem has been demonstrated to be similar in adult and pediatric subjects [23] 
[40].
In addition, the use of meropenem in this trial will allow for an adequately-sized safety 
database when data from this trial are pooled with data from the companion Phase 2 trial of 
ceftolozane/tazobactam 
(plus 
metronidazole) 
in 
pediatric 
subjects 
with 
cIAI 
(MK-7625A-035), which also utilizes meropenem as the comparator (see Section 4.2.1.1 -
1.1.1.1 Rationale for Sample Size). Available Phase 3 comparative safety data for 
ceftolozane/tazobactam versus meropenem from trials in adults with cIAI [41] will allow for 
comparison of the safety profiles of ceftolozane/tazobactam and meropenem in pediatric and 
adult subjects.
In the Phase 3 trials of ceftolozane/tazobactam in adults with cUTI (CXA-cUTI-10-04 
[MK-7625A-005] and CXA-cUTI-10-05 [MK-7625A-006]), the active comparator was a 
fluoroquinolone (levofloxacin) [21]. However, fluoroquinolones may not be appropriate as 
comparators in the pediatric population due to concerns about increased musculoskeletal AEs 
in pediatric patients who receive fluoroquinolones compared with other classes of antibiotics 
[42]. In addition, rising rates of fluoroquinolone resistance among common uropathogens have 
rendered this class of antibacterial agents a questionable choice for initial empiric therapy in 
certain parts of the world [21] [33] [43].
Rationale for Comparator Dosage
The meropenem dose for Groups 1 through 5 (20 mg/kg IV every 8 hours [maximum of 
1 g/dose]) was chosen for this trial based on the approved dosage regimen for the treatment of 
cUTI for pediatric patients 3 months to 18 years of age [23].
Safety and efficacy data of meropenem in pediatric patients under 3 months of age are limited, 
and the optimal dose regimen for this age group has not been identified. However, a trial in 
200 critically ill preterm and term infants (<91 days of age) with suspected or confirmed IAI 
 
 
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demonstrated that meropenem was safe and well tolerated at the 20 mg/kg dose [44]. Limited 
data on the PK of meropenem suggest that drug disposition in young infants may differ 
significantly from that in adults, likely related to developmental differences in renal function 
and differences in body composition seen in young infants. As a result, some sources 
recommend higher meropenem doses (up to 30 mg/kg IV every 8 hours) for the treatment of 
serious infections in neonates [45]. In order to accommodate potential variations in standard 
of care dosing, the protocol allows for a range of weight-based dosing schemes between 20 
mg/kg and 30 mg/kg for subjects in Group 5 (birth [defined as >32 weeks gestational age and 
≥7 days postnatal] to <3 months of age).
To ensure blinding, each dose of meropenem will be administered as a 60-minute 
(±10 minutes) infusion (versus the 30-minute infusion noted in the EU Product Circular [23])
to match the duration of infusion of ceftolozane/tazobactam. As described in Section 4.1.4 –
Information on Other Trial-related Therapy, the efficacy of meropenem, like other β-lactam 
antibiotics, is dependent on the T>MIC of the pathogens being treated. Therefore, the efficacy 
of meropenem is not affected by prolonging the infusion. In addition, infusions of meropenem 
longer than 1 hour have been administered to patients with satisfactory results and without 
additional safety or tolerability risk [46].
Therefore, the Sponsor believes the dosage regimen of meropenem in this trial is a clinically 
appropriate and acceptable comparator with which to evaluate the safety and efficacy of 
ceftolozane/tazobactam in pediatric cUTI.
Rationale for Duration of Therapy and Optional Oral Step-Down Antibiotic 
Therapy
Appropriate duration of therapy for pediatric cUTI treatment remains controversial, but most 
guidelines suggest 7 to 14 days of antibiotic therapy with the option of switching from 
parenteral to oral antibiotics when the patient is afebrile and/or improving [1] [2] [5] [14]. 
Thus, subjects in the present trial will receive 7 to 14 days of study treatment with the potential 
to receive oral step-down therapy after IV study treatment, in alignment with standard clinical 
practice for cUTI.
After receiving at least 9 doses of IV study treatment, subjects may be switched to oral step-
down therapy at the investigator’s discretion based on the subject’s clinical condition (Section 
5.2.2 – Optional Oral Step-down Therapy). The requirement of 72 hours (9 doses) of IV study 
treatment allows for evaluation of the safety, efficacy, and PK of ceftolozane/tazobactam while 
minimizing the need for prolonged hospitalization and IV access.
Rationale for Endpoints
Rationale for Safety Endpoints
To evaluate the safety and tolerability of ceftolozane/tazobactam in pediatric subjects, the 
incidence, severity, and type of AEs will be tabulated (see Section 7.2 – Assessing and 
Recording Adverse Events).
 
 
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Laboratory data will be summarized by the type of laboratory test. Descriptive statistics of 
temperature, heart rate, respiratory rate, and blood pressure (systolic and diastolic) values and 
changes from baseline will be summarized at each scheduled timepoint.
Subjects may be asked to return for unscheduled visits in order to perform additional safety 
monitoring.
See Section 8.4.1 – Safety Endpoints for details about the analysis of safety endpoints and 
Section 8.5.1 – Efficacy Endpoints for details about the safety analysis population.
Rationale for Efficacy Endpoints
Because the mechanism of action and the potency of ceftolozane/tazobactam should be the 
same across all ages, adult and pediatric PK data can be compared to extrapolate the efficacy 
of ceftolozane/tazobactam from adult subjects to pediatric subjects. Therefore, efficacy is 
evaluated as secondary and exploratory objectives in this trial. There are no prespecified 
statistical hypotheses for this trial. The trial is not powered to statistically compare the efficacy 
of ceftolozane/tazobactam versus meropenem.
The secondary efficacy endpoints are:

Clinical success rate at the EOT and TOC Visits, defined as the proportion of subjects 
in the analysis population who have a clinical response of cure.

Per-subject microbiological eradication rate at the EOT and TOC Visits, defined as the 
proportion of subjects in the analysis population who have an overall outcome of 
microbiological eradication.
The exploratory efficacy endpoints are:

Clinical success rate at the EOIV Visit, defined as the proportion of subjects in the 
analysis population who have a clinical response of cure or partial improvement.
NOTE: At EOIV, clinical success is defined as cure or partial improvement. At EOT 
and TOC, clinical success is defined as cure. The definition for clinical success at the 
EOIV Visit includes partial improvement to accommodate those subjects with partial 
improvement who are switched to oral step-down therapy at this time point. 

Per-subject microbiological eradication rate at the EOIV Visit.

Per-pathogen microbiological eradication rate at the EOIV, EOT, and TOC Visits, 
defined as the proportion of pathogens in the analysis population that have an outcome 
of microbiological eradication.

Composite success (clinical success and per-subject microbiological eradication) rate 
at the EOIV, EOT, and TOC Visits.
NOTE: For subjects who receive IV study treatment only (without optional oral step-down 
therapy), a separate assessment does not need to be performed at the EOT Visit; the EOIV 
Visit will serve as the EOT Visit.
 
 
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4.2.3.2.1 Clinical Outcome
Investigators will determine clinical outcomes at the EOIV, EOT, and TOC Visits according 
to the definitions in Table 3. Subjects with failure or indeterminate outcomes will be 
considered to have an unfavorable clinical response. Subjects with no study-qualifying 
baseline urine culture must be withdrawn from study treatment by the investigator 
immediately; no clinical outcome assessments of these subjects are required (see Section 5.1.2 
– Subject Inclusion Criteria).
For subjects who receive only IV study treatment and are not switched to oral step-down 
therapy, the EOIV assessment serves as the EOT assessment and these subjects do not have a 
separate EOT assessment. Subjects who are switched to oral step-down therapy will have both 
an EOIV and EOT assessment.
At EOIV, clinical success is defined as cure or partial improvement. At EOT and TOC, clinical 
success is defined as cure. Subjects with failure or indeterminate clinical outcomes will be 
considered to have an unfavorable clinical response.
Failure will be carried forward; subjects who are assessed as a failure prior to the TOC Visit
should have “failure” recorded on the TOC Visit electronic case report form (eCRF). These 
subjects should attend the TOC Visit but will not have a new clinical outcome assessment at 
this visit.
Subjects who discontinue IV study treatment or discontinue from the trial prior to receiving 9 
doses of IV study treatment for reasons other than those meeting the definition of failure will
be assessed with a clinical outcome of indeterminate. See also Section 5.8 – Subject 
Withdrawal/Discontinuation Criteria, Section 7.1.4.1 – Withdrawal/Discontinuation, and 
Section 7.1.5.9 – Subjects Who Prematurely Discontinue From Study Treatment or the Trial.
 
 
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Table 3
Clinical Outcome Categories
Outcome
Definition
Cure
Complete resolution or marked improvement in signs and symptoms of 
the cUTI or return to preinfection signs and symptoms, such that no 
further antibiotic therapy (IV or oral) is required for the treatment of 
the cUTI.
Partial improvement
(only at the EOIV Visit for subjects 
who switch to oral step-down 
therapy)
Partial resolution of signs and symptoms of the cUTI such that no 
further IV antibiotic therapy is required for the treatment of the cUTI; 
however, additional oral step-down therapy is required.
Failure
Any of the following is considered a clinical outcome of failure:

Persistence or reappearance of 1 or more sign or symptom of 
infection that requires alternative nonstudy treatment for the 
current cUTI

New signs or symptoms of infection that require alternative 
nonstudy treatment for the treatment of a cUTI due to an 
appropriate gram-negative uropathogen a

Requirement of antibiotic therapy beyond the protocol-defined 
treatment duration of 14 days

Death related to cUTI
Indeterminate
Trial data are not available for evaluation of efficacy for any reason, 
including death during the trial period unrelated to the cUTI or 
extenuating circumstances which preclude classification as cure, partial 
improvement, or failure (eg, subject is lost to follow-up).
cUTI = complicated urinary tract infection; EOIV = End of IV Treatment; IV = intravenous
a
Refer to Section 7.1.3.5 – Urine Samples for Culture for more detail about appropriate gram-negative 
uropathogens.
4.2.3.2.2 Microbiological Outcome
All microbiological outcomes will be based on laboratory results and determined by the 
Sponsor. Investigators are not responsible for assessment of microbiological outcomes.
Per-subject Microbiological Outcome
An overall microbiological response will be determined for each subject based on the 
individual microbiological response for each baseline pathogen. Microbiological response 
categories are eradication, persistence, and indeterminate as defined in Table 4. Eradication 
will be considered a favorable microbiological response; in order for the subject to have a 
favorable overall microbiological response (ie, eradication), each baseline pathogen must have 
a favorable microbiological outcome.
 
 
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Table 4
Microbiological Outcome Categories
Outcome a
Definitiona
Eradication
A postbaseline urine culture shows all uropathogens found at baseline 
at ≥105 CFU/mL are reduced to <104 CFU/mL.
Persistence
A postbaseline urine culture shows the uropathogen(s) found at 
baseline at ≥105 CFU/mL persist(s) at ≥104 CFU/mL.
Indeterminate
No appropriate urine culture result available.
CFU = colony-forming units
a
The per-pathogen microbiological outcome will be determined for each uropathogen isolated by the 
Sponsor from a baseline study-qualifying culture.
b.
Eradication will be considered a favorable microbiological response.
Composite Clinical and Microbiological Outcome
Composite clinical and microbiological outcomes will be determined as cure, failure, or 
indeterminate as defined in Table 5. If one of the outcomes is failure (clinical) or persistence 
(microbiological) and the other is indeterminate, the composite response of the subject will be 
considered failure. If one of the outcomes is cure (clinical) or eradication (microbiological)
and the other is indeterminate, the composite response of the subject will be considered 
indeterminate.
Table 5
Composite Clinical and Microbiological Outcome Categories
Outcome
Definition
Cure
Clinical response is clinical success and per-subject microbiological 
response is eradication.
Failure
Clinical response is clinical failure and/or per-subject microbiological 
response is persistence. If one of the outcomes is failure (clinical) or 
persistence (microbiological) and the other is indeterminate, the 
composite response of the subject will be considered failure.
Indeterminate
Clinical response is indeterminate and/or per-subject microbiological 
response is indeterminate. If one of the outcomes is cure (clinical) or 
eradication (microbiological) and the other is indeterminate, the 
composite response of the subject will be considered indeterminate.
Per-pathogen Microbiological Outcome
The per-pathogen microbiological outcome will be determined for each uropathogen isolated 
by the Sponsor from a baseline study-qualifying culture (see Table 4). Eradication will be 
considered a favorable microbiological response.
 
 
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Emergent Infection
Pathogens isolated after baseline will be assessed for the outcome of superinfection or new 
infection, as defined in Table 6. 
Table 6
Emergent Infection Categories
Outcome
Definition
Superinfection
A urine culture grows ≥105 CFU/mL of an appropriate gram-negative
uropathogena other than the baseline uropathogen(s) during the course 
of study treatment.
New infection
A urine culture grows ≥105 CFU/mL of an appropriate gram-negative
uropathogena other than the baseline uropathogen(s) after 
administration of the last dose of study treatment and through the 
TOC visit.
CFU = colony-forming units
a
Refer to Section 7.1.3.5 – Urine Samples for Culture for more detail about appropriate gram-negative
uropathogens.
See Section 8.4.2 - Efficacy Endpoints for details about efficacy analyses and Section 8.5.2 -
Efficacy Analysis Populations for details about the efficacy analysis populations.
Rationale for Pharmacokinetic Endpoints
Whole blood samples (250 µL) will be collected at the time points specified in Section 6.0 –
Trial Flow Chart for determination of plasma concentrations of ceftolozane, tazobactam, and
tazobactam
M1. Specific information about PK sample collection is provided in 
Section 7.1.3.7 – Pharmacokinetic Evaluations. These samples will provide pediatric PK data 
in the target population and will support further evaluation of the PK profiles of ceftolozane 
and tazobactam by confirming whether subjects achieve percentage of dosing interval during 
which free concentration of drug (ceftolozane) exceeds the MIC (% fT>MIC) of at least 30% 
(for an MIC of 4 µg/mL) for ceftolozane and percentage of dosing interval during which free 
concentration of drug (tazobactam) exceeds the Ct (% fT>Ct) of at least 20% (for a threshold 
concentration of 1 µg/mL) for tazobactam.
Pharmacokinetic data may also aid in the assessment of the clinical relationship between 
ceftolozane and tazobactam plasma concentrations and efficacy in the pediatric population.
See Section 8.4.3 – Pharmacokinetic Endpoints for details about analysis of PK endpoints.
Benefit/Risk
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment during 
participation, as clinical trials are designed to provide information about the safety and 
effectiveness of an investigational medicine.
 
 
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This trial will include pediatric subjects who require IV antibiotics for treatment of cUTI. If 
randomized to receive ceftolozane/tazobactam, subjects will receive an antibiotic regimen that 
is active against organisms commonly isolated from pediatric patients with cUTI and that has 
proven to be effective in large-scale clinical trials for the treatment of cUTI in adults (Section 
4.1.1.1 – Ceftolozane/Tazobactam). Subjects who are randomized to the comparator arm will 
receive meropenem, an antibacterial agent approved for treatment of cUTI in pediatric patients
3 months of age and older and adults (Section 4.1.4 – Information on Other Trial-Related 
Therapy).
Although potentially more frequent than the standard of care, the planned study procedures 
(see Section 6.0 – Trial Flow Chart) are generally typical procedures performed for this patient 
population. Trial procedures, including the number of blood draws for PK sampling, are 
limited in order to minimize risk. Additional burden may be incurred due to visits after release 
from the hospital; however, the procedures performed at these visits are generally not likely to 
lead to significant harm (eg, blood draws, urine collection, physical examinations, and vital 
signs) and are necessary to support a robust evaluation of the safety and efficacy of the 
investigational drug.
Additional details regarding specific benefits and risks for subjects participating in this clinical 
trial may be found in the accompanying ceftolozane/tazobactam IB and Informed Consent 
documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male and female subjects from birth (defined as >32 weeks gestational age and ≥7 days 
postnatal) to <18 years of age with cUTI will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Have a legally acceptable representative who provides documented informed 
consent/assent for the trial.
2. Be a male or female from birth (defined as >32 weeks gestational age and ≥7 days 
postnatal) to <18 years of age.
NOTE: In Ukraine, enrollment age of a male or female subject is limited to 3 months 
to < 18 years (Groups 1-4). Subjects < 3 months old (Group 5) are not permitted to 
enroll into the study at Ukraine sites.
3. Be able to comply with the protocol for the duration of the trial.
4. Require IV antibacterial therapy for the treatment of cUTI.
5. Have a pretreatment baseline urine culture specimen obtained within 48 hours before 
the start of administration of the first dose of study treatment and preferably prior to 
 
 
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administration of any potentially therapeutic antibiotics. Specimen is to be obtained 
by suprapubic aspiration, clean intermittent urethral catheterization, indwelling 
urethral catheter, or mid-stream clean catch.
NOTE: Subjects may be enrolled in this trial and start IV study treatment before the 
investigator knows the results of the baseline urine culture; however, subjects without 
documented ≥105 colony-forming units (CFU)/mL of an appropriate gram-negative 
uropathogen cultured from a baseline urine specimen must discontinue study 
treatment immediately following culture result.
6. Have pyuria, defined as dipstick analysis positive for leukocyte esterase, OR:
a) If ≥1 year of age: White blood cell (WBC) count >10 cells/µL in unspun urine or 
≥10 cells/high power field in spun urine
b) If <1 year of age: WBC count >5 cells/µL in unspun urine or ≥5 cells/high power 
field in spun urine
7. Have clinical signs and/or symptoms of cUTI (pyelonephritis or cLUTI) at the
Screening Visit.
a) For pyelonephritis, subjects must have at least 2 of the following new or 
worsening signs and/or symptoms:
i. If 0 to <2 years of age:
-Fever (as defined by the investigator)
-Failure to thrive
-Recent weight loss
-Irritability
-Poor feeding
-Lack of normal level of activity
-Abdominal tenderness on physical examination
-Vomiting
-Jaundice
ii. If 2 to <18 years of age:
-Fever (as defined by the investigator)
-Dysuria
-Urinary urgency
-Urinary frequency
-New-onset urinary incontinence
-Suprapubic pain, flank pain, or abdominal pain
-Suprapubic tenderness or CVA tenderness on physical examination
-Nausea or vomiting
OR
b) For cLUTI, subjects must have at least 2 of the new or worsening signs and/or 
symptoms listed above AND must have at least 1 of the following complicating 
factors:
-Obstructive uropathy
-Congenital, functional, or anatomic abnormality of the urogenital tract
 
 
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-Temporary indwelling urinary catheter
-Bladder instrumentation within <24 hours
-Recurrent UTI (≥2 events within a 12-month period) 
8. Meet one of the following categories:
a) The subject is a male who is not of reproductive potential, defined as a male who 
has azoospermia (whether due to being prepubertal, having had a vasectomy, or 
an underlying medical condition).
b) The subject is a female who is not of reproductive potential, defined as a female 
who either: (1) Has not undergone menarche; (2) has had a hysterectomy and/or 
bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal 
ligation/occlusion at least 6 weeks prior to screening, or (3) has a congenital or 
acquired condition that prevents child-bearing.
c) The subject is a female or a male of reproductive potential who agrees to avoid 
becoming pregnant or impregnating a partner during screening, while receiving 
study treatment, and for at least 30 days after the last dose of study treatment by 
complying with one of the following: (1) Practice abstinencea from heterosexual 
activity OR (2) use (or have their partner use) acceptable contraception during 
heterosexual activity. Acceptable methods of contraception areb:
Single method (1 of the following is acceptable):

Intrauterine device (IUD)

Vasectomy of a female subject’s male partner 

Contraceptive rod implanted into the skin
Combination method (requires use of 2 of the following):

Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

Cervical cap with spermicide (nulliparous females only)

Contraceptive sponge (nulliparous females only)

Male condom or female condom (cannot be used together)

Hormonal contraceptive: Oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, 
or subcutaneous contraceptive injection
a
Abstinence (relative to heterosexual activity) can be used as the sole method 
of contraception if it is consistently employed as the subject’s preferred and 
usual lifestyle and if considered acceptable by local regulatory agencies and 
Ethics Review Committees (ERCs)/Institutional Review Boards (IRBs). 
Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.
b
If a contraceptive method listed above is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable method of 
contraception for subjects participating at sites in this country/region.
 
 
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9. Meet the following criteria for a female subject who is of reproductive potential:
a) The subject is not pregnant (as confirmed by serum pregnancy test at screening) 
and not planning to become pregnant within 30 days of the last day of study 
treatment administration,
AND
b) The subject is nonlactating.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating in or has participated in an interventional clinical trial with an 
investigational compound or device within 30 days prior to the first dose of study 
treatment in this current trial.
2. Has previously participated in any trial of ceftolozane or ceftolozane/tazobactam or has 
enrolled previously in the current trial and been discontinued.
3. Has a history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that, in the opinion of the investigator, might expose the subject to 
increased risk by participating in the trial, confound the results of the trial, or interfere 
with the subject’s participation for the full duration of the trial.
4. Has a history of any moderate or severe hypersensitivity (eg, anaphylaxis), allergic 
reaction, or other contraindication to any of the following: β-lactam antibiotics 
(eg, penicillins, cephalosporins and carbapenems), or β-lactamase inhibitors 
(eg, tazobactam, sulbactam, clavulanic acid, avibactam).
NOTE: A history of mild rash to any of these agents is not a contraindication to 
enrollment.
5. Has a history of a cUTI within the past 1 year prior to randomization that is caused by 
a pathogen known to be resistant to either IV study treatment.
6. Has a concomitant infection at the time of randomization that requires nonstudy 
systemic antibacterial therapy in addition to IV study treatment or oral step-down 
therapy (medications with only gram-positive activity [eg, vancomycin, linezolid] are 
allowed).
 
 
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7. Has received potentially therapeutic antibacterial therapy (eg, with gram-negative 
activity), including bladder infusions with topical urinary antiseptics or antibacterial 
agents, for a duration of more than 24 hours during the 48 hours preceding the first 
dose of study treatment.
NOTE: Provided all other eligibility criteria are met, including obtaining a baseline 
study-qualifying urine culture, the following subjects may be enrolled; however, 
subjects without documented ≥105 CFU/mL of an appropriate gram-negative
uropathogen must discontinue study treatment immediately following culture results:
a) Subjects with an active cUTI who received at least 48 hours of a prior antibiotic 
regimen, if in the opinion of the investigator there is evidence they are failing 
the prior antibiotic regimen.
b) Subjects who are receiving antibiotic prophylaxis for cUTI who present with 
signs and symptoms consistent with an active new cUTI due to an appropriate 
gram-negative uropathogen.
8. Has any of the following:
a) Intractable UTI or pyelonephritis infection at baseline that the Investigator 
anticipates would require more than 14 days of study treatment
b) Confirmed fungal urinary tract infection at time of randomization with ≥103
fungal CFU/mL
c) Permanent indwelling bladder catheter or instrumentation including 
nephrostomy
d) Current urinary catheter that is not scheduled to be removed before the end of 
all study treatment (intermittent straight catheterization during the study 
treatment period is acceptable)
e) Complete, permanent obstruction of the urinary tract
f)
Suspected or confirmed perinephric or intrarenal abscess
g) Documented ileal loop reflux
h) Suspected or confirmed prostatitis, urethritis, or epididymitis
i)
Trauma to pelvis/urinary tract
9. Has moderate or severe impairment of renal function, defined as an estimated creatinine 
clearance (CrCL) <50 mL/min/1.73 m2 based on the revised Schwartz equation [24] or 
requirement for peritoneal dialysis, hemodialysis, or hemofiltration.
10. Has one or more of the following laboratory abnormalities in a specimen obtained at 
baseline:
a) Absolute neutrophil count (ANC) <1000/mm3
b) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 × the 
upper limit of normal (ULN)
c) Total bilirubin ≥2 × ULN (if 7 to ≤28 days of age and breastfeeding, total 
bilirubin >10 mg/dL OR ≥2 × ULN)
11. Has a seizure disorder or is anticipated to be treated with divalproex sodium or valproic 
acid during the course of study treatment.
12. Is receiving, or is expected to receive, any of the following medications:
 
 
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a) Immunosuppressive agents
NOTE: Short-term treatment with systemic (IV or oral) steroids of <1 week 
duration (eg, treatment for an acute asthma exacerbation or acute skin 
condition) is allowed. Topical steroids for the treatment of skin conditions are 
also allowed.
b) Valproic acid or divalproex sodium 
c) Probenecid
13. Has any rapidly progressing disease or immediately life-threatening illness including 
acute hepatic failure, respiratory failure, or septic shock.
14. Has an immunocompromising condition, including established AIDS, hematological 
malignancy, or bone marrow transplantation, or is receiving immunosuppressive 
therapy including cancer chemotherapy, medications for prevention of organ 
transplantation rejection, or chronic administration of systemic corticosteroids (defined 
as the systemic equivalent of ≥2 mg/kg total daily dose of prednisone for participants 
≤20 kg, or >40 mg of prednisone per day for participants >20 kg, administered 
continuously for more than 14 days in the 30 days prior to the first dose of 
ceftolozane/tazobactam)
15. Has a history of malignancy ≤5 years prior to providing documented informed consent, 
except for adequately treated basal cell or squamous cell skin cancer or in situ cervical 
cancer.
16. Planned receipt of suppressive/prophylactic antibiotics with gram-negative activity 
after completion of study treatment.
NOTE: Based on site level standard of care, subjects at increased risk of recurrent 
pyelonephritis or cUTI (eg, vesico-ureteral reflux Grade 3 through 5) wherein there is 
a clear benefit to low-dose antibiotic prophylaxis, may be enrolled.
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or Sponsor staff directly involved with this trial.
Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 7 and Table 8. 
Intravenous Trial Treatments
The IV treatment regimens to be used in this trial are outlined in Table 7.
After receiving at least 9 doses of double-blind IV study treatment, subjects in either treatment 
arm may be switched to open-label, standard-of-care oral step-down antibiotic therapy at the
investigator’s discretion (Section 5.2.2 – Optional Oral Step-down Therapy). Total antibiotic 
duration (IV only or IV + oral) is a minimum of 7 and a maximum of 14 days.
NOTE: In Ukraine, enrollment will be limited to subjects 3 months to < 18 years of age 
(Groups 1-4). Study treatments for Group 5 are not applicable at Ukrainian sites.
 
 
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Table 7
Intravenous Trial Treatments
Drug
Dose/Potency
Dose 
Frequency a
Route of 
Administration b
Treatment 
Period b
Use
Age Group 1 (12 to <18 years [n≥50 combined with Group 2]) c
Ceftolozane
/tazobactam
Ceftolozane 1 g 
and tazobactam 
0.5 g
Every 8 hours
IV
7-14 days
Experimental
Meropenem
20 mg/kg 
(maximum 
1 g/dose)
Every 8 hours
IV
7-14 days
Active
comparator
Age Group 2 (6 to <12 years [n≥50 combined with Group 1]) c
Ceftolozane
/tazobactam
Ceftolozane 
20 mg/kg and 
tazobactam 
10 mg/kg
(maximum 
ceftolozane 1 g 
and tazobactam 
0.5 g/dose)
Every 8 hours
IV
7-14 days
Experimental
Meropenem
20 mg/kg 
(maximum 
1 g/dose)
Every 8 hours
IV
7-14 days
Active
comparator
Age Group 3 (2 to <6 years [n≥57 combined with same age group in MK-7625A-035]) c
Ceftolozane
/tazobactam
Ceftolozane 
20 mg/kg and 
tazobactam 
10 mg/kg
(maximum 
ceftolozane 1 g 
and tazobactam 
0.5 g/dose)
Every 8 hours
IV
7-14 days
Experimental
Meropenem
20 mg/kg 
(maximum 
1 g/dose)
Every 8 hours
IV
7-14 days
Active
comparator
Age Group 4 (3 months to <2 years [n≥24 combined with same age group in MK-7625A-035]) c
Ceftolozane
/tazobactam
Ceftolozane 
20 mg/kg and 
tazobactam 
10 mg/kg
(maximum 
ceftolozane 1 g 
and tazobactam 
0.5 g/dose)
Every 8 hours
IV
7-14 days
Experimental
Meropenem
20 mg/kg 
(maximum 
1 g/dose)
Every 8 hours
IV
7-14 days
Active
comparator
 
 
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Drug
Dose/Potency
Dose 
Frequency a
Route of 
Administration b
Treatment 
Period b
Use
Age Group 5 (Birthd to <3 months [n≥21 combined with same age group in MK-7625A-035]) c
Ceftolozane
/tazobactam
Ceftolozane 
20 mg/kg and 
tazobactam 
10 mg/kg
(maximum 
ceftolozane 1 g 
and tazobactam 
0.5 g/dose)
Every 8 hours
IV
7-14 days
Experimental
Meropenem
20 mg/kg 
(maximum 
1 g/dose) e
Every 8 hours
IV
7-14 days
Active
comparator
IV = intravenous
a
Each dose of ceftolozane/tazobactam or meropenem is administered as a 60-minute (±10 minutes)
infusion. Ceftolozane/tazobactam and meropenem are to be dosed every 8 hours (±1 hour) after the 
previous infusion. The second IV dose has a ±4-hour window for dosing to facilitate adjustment of the IV 
dosing schedule (once every 8 hours) to be performed throughout the IV dosing period.
b
After receiving at least 9 doses of double-blind IV study treatment, subjects may be switched to open-
label, standard-of-care, oral step-down therapy at the investigator’s discretion. The total duration of study 
treatment (IV only or IV + oral) is a minimum of 7 days and a maximum of 14 days.
c
The total minimum number of subjects in the 5 age groups combined across MK-7625A-034 and MK-
7625A-035 is 202. After the minimum enrollment targets for each age group are met, additional subjects 
(combined across MK-7625A-034 and MK-7625A-035) will be enrolled in any of the 5 age groups.
d
Birth is defined as >32 weeks gestational age and ≥7 days postnatal.
e
Some literature supports a higher meropenem dosage (up to 30 mg/kg every 8 hours) for subjects 14 days 
to <3 months of age, therefore meropenem dosing up to 30 mg/kg every 8 hours may be used for subjects 
14 days to <3 months of age at the investigator’s discretion.
Optional Oral Step-down Therapy
After receiving at least 9 doses of double-blind IV study treatment, subjects may be switched 
to open-label, standard-of-care, oral step-down antibiotic therapy at the investigator’s 
discretion. Total antibiotic duration (IV only or IV + oral) is a minimum of 7 to a maximum of 
14 days. Optional oral step-down therapy is considered study treatment in this trial.
Oral step-down therapy should be guided by culture results and consistent with the local 
standard of care. Table 8 lists recommended options for oral step-down therapy.
 
 
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Table 8
Recommended Oral Step-down Therapy Options
Antibiotic or Antibiotic Classa
β-lactam/β-lactamase inhibitor combination
Cephalosporin
Quinolone
Nitrofurantoin
Trimethoprim or trimethoprim/sulfamethoxazole
a
The choice of oral step-down therapy should be guided by culture results and based on local antibiotic 
susceptibility patterns.
NOTE: Regimens not listed above must be approved by the Sponsor.
Trial Treatments: Administrative Considerations
Trial treatment should begin as soon as possible after randomization and at the latest within 
24 hours of randomization. There should be no medically inappropriate delay in randomization 
and subsequent study treatment.
All supplies indicated in Table 7 and Table 8 will be provided centrally by the Sponsor or 
locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements.
For any commercially available product that is provided by the trial site, subsidiary or designee 
every attempt will be made to source these supplies from a single lot/batch number. The trial 
site is responsible for recording the lot number, manufacturer, and expiry date for any locally 
purchased product as per local guidelines unless otherwise instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
Dose Selection (Preparation)
The following doses are to be used in this trial:

12 to <18 years of age: Ceftolozane 1 g with tazobactam 0.5 g via a 60-minute 
(±10 minutes) IV infusion every 8 hours

<12 years of age: Ceftolozane 20 mg/kg with tazobactam 10 mg/kg via a 60-minute
(±10 minutes) IV infusion every 8 hours (not to exceed a dose of ceftolozane 1 g and 
tazobactam 0.5 g)
 
 
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The rationale for selection of doses to be used in this trial is provided in Section 4.2.2 –
Rationale for Dose Selection/Regimen. The dosing calculations and drug preparation are 
described in detail in the pharmacy manual.
Timing of Dose Administration
Ceftolozane/tazobactam and meropenem are to be dosed every 8 hours (±1 hour) after the 
previous infusion. The second IV dose has a ±4-hour window for dosing to facilitate 
adjustment of the dosing schedule (once every 8 hours) to be carried out throughout the IV 
dosing period.
The final day of study treatment may extend into Day 15 to accommodate different start and 
stop times of the IV study treatment and/or dosing schedules of the oral step-down therapy.
Trial Blinding 
A double-blinding technique with in-house blinding will be used.  Ceftolozane/tazobactam and 
meropenem will be packaged identically so that blinding is maintained.
The subject, the 
investigator and Sponsor personnel or delegate(s) who are involved in the treatment or clinical 
evaluation of the subjects are unaware of the group assignments.
An unblinded pharmacist will prepare IV study treatment. In addition, infusion bags, IV lines, 
and any other dispensing devices will be covered as needed to maintain blinding.
The standard-of-care oral step-down therapy used at the discretion of the investigator after 
completion of IV study treatment will not be blinded.
Specific blinding procedures required for this study can be found in the pharmacy manual.
See Section 7.1.4.4, Subject Blinding/Unblinding, for a description of the method of 
unblinding a subject during the trial, should such action be warranted.
Randomization
Treatment randomization will occur centrally using an interactive voice response system / 
integrated web response system (IVRS/IWRS). There are 2 treatment arms.  Subjects will be 
assigned randomly in a 3:1 ratio to ceftolozane/tazobactam or meropenem, respectively.
Stratification
Treatment randomization will be stratified across 5 age groups as defined in Section 2.1 – Trial 
Design. After the minimum enrollment targets in Section 2.1 for each age group are met (202 
subjects total), additional subjects (combined across MK-7625A-034 and MK-7625A-035) 
will be enrolled in any of the 5 age groups.
 
 
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Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications specifically prohibited in the exclusion criteria are not allowed during the ongoing 
trial. If there is a clinical indication for any medication specifically prohibited during the trial, 
discontinuation from trial therapy may be required. The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director. The final decision on any 
supportive therapy rests with the investigator and/or the subject’s primary physician; however, 
the decision to continue the subject on trial therapy requires the mutual agreement of the 
investigator, the Sponsor, and subject/subject’s legal representative.
The following concomitant medications/therapies are not permitted in this study:

Immunosuppressive agents
NOTE: Short-term treatment with systemic (IV or oral) steroids of <1 week duration 
(eg, treatment for an acute asthma exacerbation or acute skin condition) is allowed. 
Topical steroids for the treatment of skin conditions are also allowed.

Valproic acid or divalproex sodium

Probenecid

Concomitant systemic antibacterial agents with gram-negative activity, other than 
1 dose of prophylactic antibiotic, are not permitted while the subject is receiving IV 
study treatment or oral step-down therapy. Use of such agents for any reason other than 
the subject being considered a clinical failure must be discussed with the Sponsor 
Clinical Director before administration.

Bladder infusions with topical urinary antiseptics or antibacterial agents are not 
permitted. Subjects who require such therapy will be considered clinical failures.
All other concomitant medications necessary for the health and well-being of the subject are 
permitted.
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
Intravenous study treatment may be administered without regard to food, alcohol, or caffeine 
consumption, tobacco use, or activity. Oral step-down study therapy may have different dietary
considerations from IV study treatment and should be administered according to the product 
label.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of IV study treatment or oral step-down therapy does not represent withdrawal 
from the trial.
 
 
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As certain data on clinical events beyond study treatment discontinuation are important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the subject 
has discontinued study treatment.  Therefore, all subjects who discontinue trial treatment prior 
to completion of the treatment period will still continue to participate in the trial as specified 
in Section 6.0 – Trial Flow Chart and Section 7.1.5.9 – Subjects Who Prematurely Discontinue
from Study Treatment or the Trial.
Subjects may discontinue study treatment at any time for any reason or be dropped from study 
treatment at the discretion of the investigator should any untoward effect occur.  In addition, a 
subject may be discontinued from study treatment by the investigator or the Sponsor if study 
treatment is inappropriate, the trial plan is violated, or for administrative and/or other safety 
reasons.  Specific details regarding procedures to be performed at study treatment
discontinuation are provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from IV study treatment or oral step-down therapy but 
continue to be monitored in the trial for any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue study 
treatment.
o
Lack of study-qualifying baseline urine culture. Subjects whose baseline urine culture does 
not qualify as defined in Section 7.1.3 – Laboratory Procedures/Assessments must be 
discontinued from study treatment by the investigator immediately. At the time study 
treatment is discontinued, all EOT Visit procedures must be completed and recorded in the 
eCRF. No clinical response assessments or follow-up urine cultures are required for this 
category of subjects; however, these subjects should return to the trial site for the TOC 
Visit 5 to 9 days after administration of the last dose of study treatment, and return or be 
contacted for the LFU Visit 28 to 35 days after administration of the last dose of study 
treatment to complete safety assessments including assessment of AEs, recording 
concomitant medications, and collection of standard safety laboratory data. Collection of 
standard safety laboratory data is required at LFU only if abnormal values existed at the 
prior visit.
o
The subject has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or Sponsor, places the subject at unnecessary risk from continued 
administration of study treatment.
o
Development of moderate or severe impairment of renal function, including an estimated 
CrCL <50 mL/min/1.73 m2 based on the revised Schwartz equation [24] or requirement for 
peritoneal dialysis, hemodialysis, or hemofiltration (required for IV study treatment only).
o
The investigator feels it is in the best interest of the subject to discontinue for any reason, 
including, but not limited to, the need for nonstudy antibacterial therapy due to insufficient 
therapeutic effect of the study treatment.
o
Safety issues:

Occurrence of an AE or clinically significant laboratory abnormality that, in the opinion 
of the Investigator, warrants the subject’s permanent discontinuation from IV study 
treatment or oral step-down therapy. In the event that IV study treatment or oral step-
 
 
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down therapy is discontinued due to the occurrence of an AE, the trial site should notify 
the Sponsor as soon as possible.

Suspected or confirmed pregnancy or breastfeeding during the IV study treatment or 
oral step-down therapy administration period. Female subjects whose pregnancy test 
becomes positive during study treatment must be followed through the immediate 
postnatal period or until termination of the pregnancy.
Discontinuation from study treatment is “permanent.” Once a subject is discontinued, he/she 
shall not be allowed to restart study treatment.
Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive study treatment or be followed 
at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, are outlined in Section 
7.1.4 – Other Procedures.
Subject Replacement Strategy
A subject who discontinues from study treatment or withdraws from the trial will not be 
replaced.
Beginning and End of the Trial
The overall trial begins when the first subject (or their legally acceptable representative) 
provides documented informed consent.  The overall trial ends when the last data are available 
in either MK-7625A-034 or MK-7625A-035 (whichever is later).
Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of emerging 
effects/clinical endpoints is such that the risk/benefit ratio to the trial population as a whole is 
unacceptable.  In addition, further recruitment in the trial or at (a) particular trial site(s) may 
be stopped due to insufficient compliance with the protocol, GCP and/or other applicable 
regulatory requirements, procedure-related problems or the number of discontinuations for 
administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
Trial Period:
Screening
Treatment (7 to 14 days) a
Follow-up
Visit Number:
1
2
3 to 16
17
18
19
20
21
Visit Title:
Screening b
Randomizationb
IV Clinical 
Assessments a,b
EOIVc
(all 
subjects)
Oral Clinical 
Assessment d,e
(only for IV to 
oral switch)
EOT d
(only for 
IV to oral 
switch)
TOC
(all subjects)
LFU f
(all subjects)
Scheduled Day or Timing:
48 h
Day 1
Day 2 up to Day 
15
<24 h 
after last 
IV dose
(after ≥7 days 
on oral step-
down therapy)
<48 h after 
last oral 
dose 
5 to 9 days 
after final 
dose
28 to 35 days 
after final 
dose
Administrative Procedures
Informed consent
X
Inclusion/exclusion criteria
X
Subject identification card
X
X
Medical history
X
Prior or concomitant medication review
X
X
X
X
X
X
X
X
Randomize to treatment (prior to 
administration of study treatment)
X
Administer ceftolozane/tazobactam IV or 
meropenem IV every 8 h
X
X
Standard-of-care oral step-down therapy a
X
Clinical Procedures/Assessments
Body weight
X
X g,h
X g,h
X g
X g,h
X g
Height
X
Vital signs (heart rate, respiratory rate, blood 
pressure, and temperature)
X
X
X
X
X
X
X
X g,i
Full physical examination
X
Directed physical examination
X j
X
X
X
X
X g,i
Sign/symptom assessment
X
X
X
X
X
X
X
AE monitoring k
X
X
X
X
X
X
X
Assess clinical outcome
X
X
X
 
 
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Trial Period:
Screening
Treatment (7 to 14 days) a
Follow-up
Visit Number:
1
2
3 to 16
17
18
19
20
21
Visit Title:
Screening b
Randomizationb
IV Clinical 
Assessments a,b
EOIVc
(all 
subjects)
Oral Clinical 
Assessment d,e
(only for IV to 
oral switch)
EOT d
(only for 
IV to oral 
switch)
TOC
(all subjects)
LFU f
(all subjects)
Scheduled Day or Timing:
48 h
Day 1
Day 2 up to Day 
15
<24 h 
after last 
IV dose
(after ≥7 days 
on oral step-
down therapy)
<48 h after 
last oral 
dose 
5 to 9 days 
after final 
dose
28 to 35 days 
after final 
dose
Laboratory Procedures/Assessments
Blood for hematology and chemistry safety 
evaluations
X
X j
X l
X
X l
X
X g,i
Coombs test (direct)
X
X
Urine microscopy for pyuria
X
X m
X m
X m
Serum pregnancy test n
X n
X n
Assessment of CrCL
X
X g
X g
X g
X g
Urine for culture and susceptibility testing
X
X m
X m
X m
Verify urine culture resulto
X o
Blood for culture and susceptibility testingg
X g
X g
X g
Blood for PK analyses (Day 3 only [after ≥6 
doses of IV study treatment]) p
X o
AE = adverse event; CFU = colony-forming units; CrCL = creatinine clearance; eCRF = electronic case report form; EOIV = End of IV Treatment; EOT = End of 
Treatment; h = hour(s); IV = intravenous; LFU = Last Follow-up; PK = pharmacokinetic(s); SAE = serious adverse event; TOC = Test of Cure
a
After receiving at least 9 doses of double-blind IV study treatment, subjects in either treatment arm may be switched to open-label, standard-of-care oral step-
down antibiotic therapy at the investigator’s discretion. Total duration of study treatment (IV only or IV + oral) is a minimum of 7 days and a maximum of 
14 days, except the final day of study treatment may extend into Day 15 to accommodate different start and stop times of the IV study treatment and/or dosing 
schedules of the oral step-down therapy. From Day 1 through the last day of IV study treatment, each subject’s assessments should be performed at a consistent 
time of day (eg, every morning) on each calendar day, as much as possible. Subjects cannot go home on IV study treatment. If subjects are switched to oral 
step-down therapy, the oral step-down therapy must be initiated <24 hours after stopping IV study treatment.
b
Screening, randomization, and first dose of study treatment may all occur on the same day. Assessments (eg, laboratory procedures, vital signs) performed prior 
to providing documented informed consent may be used if collected during the routine care of the patient, so long as they were conducted within 48 hours prior 
to the start of administration of the first dose of IV study treatment.
c
For subjects who receive only IV study treatment and are not switched to oral step-down therapy, the EOIV Visit serves as the EOT Visit and these subjects do 
not have a separate EOT Visit. Subjects who are switched to oral step-down therapy will have both an EOIV and EOT Visit.
d
Only for subjects who are switched to oral step-down therapy.
 
 
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e
An Oral Clinical Assessment Visit should be performed once if a subject receives ≥7 days of oral step-down therapy. This visit can be performed ± 24 hours 
after 7 days of oral step-down therapy. Subjects who receive <7 days of oral step-down therapy will not undergo the Oral Clinical Assessment Visit. Any AE 
that comes to the attention of the investigator before the Oral Clinical Assessment Visit should be recorded at this visit, but any SAE must be reported within 
24 hours. The Oral Clinical Assessment Visit will be the same whether the subject is still in the hospital or has been discharged to home. 
f
The LFU Visit will be conducted by telephone; however, if the subject has abnormal laboratory values or AEs that require follow-up, an in-person visit is 
required.
g
If clinically indicated.
h
As needed to calculate CrCL or changes in weight-based dosing, if the subject’s weight is expected to change over the course of IV study treatment.
i
To be performed only if LFU Visit is conducted in person instead of by telephone.
j
Procedures to be completed on Day 3 and then once weekly while the subject is receiving study treatment (IV or oral).
k
The reporting period for AEs is outlined in Section 7.2. All serious adverse events will be followed until resolution, stabilization, withdrawal of consent, or 
death.
l
If blood samples for chemistry and hematology safety evaluations were collected within 24 hours prior to this Visit, blood samples for these evaluations are not 
required.
m
The use of sterile urine collection bags is allowed for young children who are unable to provide mid-stream clean catch urine specimens at the EOIV, EOT, and 
TOC Visits. However, urine microscopy must be performed to detect pyuria in the urine sample; if pyuria is not present (as defined per inclusion criteria #6), 
then any bacterial growth may be considered a contaminant rather than a true superinfection or new infection. 
n
Female subjects of child-bearing potential only. A urine pregnancy test instead of a serum pregnancy test may be done at the TOC Visit, if deemed clinically 
appropriate by the investigator.
o
Verify results from urine culture (sample obtained at screening) at the first Clinical Assessment Visit at which results are available. Subjects who are not 
documented as having ≥105 CFU/mL of an appropriate gram-negative uropathogen cultured from a screening urine specimen must discontinue from the trial 
immediately upon receipt of the culture result. At the time study treatment is discontinued, all EOT Visit procedures must be completed and recorded in the 
eCRF.
p
Blood samples for ceftolozane, tazobactam, and tazobactam M1 concentration assays will be collected from all subjects over one 8-hour dosing period on Day 
3 of the treatment period after administration of at least 6 doses of IV study treatment (see Section 7.1.3.7 – Pharmacokinetic Evaluations). On Day 3, 250 µL 
of blood will be collected at the following times: At the end of infusion (collected within 10 minutes after the end of total dose administration); between 2.5 and 
3.5 h post start of infusion; and between 5.0 and 6.0 hours post start of infusion but prior to the start of the next dose of study treatment. If sampling on Day 3 is 
logistically difficult, sampling may be performed at comparable time points after Day 3 in subjects who are continuing to receive IV study treatment. Plasma 
will be separated from blood and sent to the central laboratory for PK testing. Procedures for collection, processing, storage, and shipment of PK samples from 
blood (plasma) will be provided separately in a laboratory manual. Actual whole blood sample collection dates and times should be recorded on the appropriate 
eCRF.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent, and assent if applicable, be obtained from the subject.  
In these cases, such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent, and assent if applicable, from each potential subject or 
each subject’s legally acceptable representative prior to participating in this clinical trial. If 
there are changes to the subject’s status during the trial (e.g., health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented consent/assent is in place. 
7.1.1.1.1 General Informed Consent/Assent
Informed consent/assent given by the subject or their legally acceptable representative must be 
documented on a consent/assent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the subject (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent/assent form should be given to the subject 
(or their legally acceptable representative) before participation in the trial.
The initial informed consent/assent form, any subsequent revised informed consent/assent
form and any written information provided to the subject must receive the IRB/IEC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised 
consent/assent form or addendum to the original consent/assent form that captures the subject’s 
or the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population are to be included in the trial informed 
consent/assent form.  
 
 
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Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations and 
Sponsor requirements.  The assent, as applicable, will adhere to IRB/ERC requirements, 
applicable laws and regulations, and Sponsor requirements.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides 
documented
informed 
consent/assent.
At 
the 
time 
of 
treatment 
allocation/randomization, site personnel will add the treatment/randomization number to the 
Subject Identification Card.
The subject identification card also contains contact information for the emergency unblinding 
call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. In addition to the 
evaluation of a subject’s medical history in terms of study eligibility, all medical conditions 
present during the 5 years prior to study entry will be documented at the Screening Visit on 
the appropriate eCRF. Any history of prior cUTI episodes or conditions that may predispose a 
subject to the development of cUTI will also be documented on the appropriate eCRF, even if 
the prior episode or predisposing condition was diagnosed more than 5 years prior to study 
entry.
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
At Screening, the investigator or qualified designee will review prior medication use and 
record prior medication taken by the subject within 7 days before the first dose of trial 
medication (or within 14 days before the first dose of trial medication for all antibacterial 
agents, and within 30 days before the first dose of trial medication for any other investigational 
drug). For subjects who are breastfeeding, prior medication use by the subject’s mother will 
be recorded similarly.
Any blood or blood product transfusions in the previous 48 hours before first dose of trial 
medication will be recorded.
 
 
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7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial (from the first dose of trial medication to the last trial evaluation). For subjects 
who are breastfeeding, concomitant medication use by the subject’s mother will be recorded 
similarly.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization.  Each subject will be assigned 
only one screening number.  Screening numbers must not be re-used for different subjects.
Specific details on the Screening Visit requirements are provided in Section 7.1.5.1 -
Screening.
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after randomization.  Once a treatment/randomization number is assigned to a 
subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance (Medication)
Interruptions from the protocol specified IV study treatment for ≥2 consecutive doses or 
≥3 nonconsecutive doses require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on subject management.
Clinical Procedures/Assessments
Clinical procedures and assessments will occur as specified in Section 6.0 – Trial Flow Chart. 
This section provides additional details. Clinical procedure/assessment data will be recorded 
in source documents and the appropriate location in the eCRF.
Body Weight, Height and Vital Signs
The investigator or qualified designee will record body weight (kg) and height (cm) as 
indicated in Section 6.0 – Trial Flow Chart. Body weight will be measured without shoes,
jacket, or diaper (in subjects using diapers).
The investigator or qualified designee will record vital signs (heart rate, respiratory rate, blood 
pressure, and temperature [oral, tympanic, rectal, axillary, or temporal]) as indicated in Section 
6.0 – Trial Flow Chart. Systolic and diastolic blood pressure will be measured on the same arm. 
Heart rate and blood pressure will be measured simultaneously.
 
 
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Physical Examination
The investigator or qualified designee will perform full or directed physical examinations as 
indicated in Section 6.0 – Trial Flow Chart. The investigator or qualified designee will also 
perform a full or directed physical examination at other times at the investigator’s discretion, 
if an AE or abnormality is suspected.
The full physical examination will include examination of body systems (including, but not 
limited to, general appearance, skin, neck, eyes, ears, nose, throat, breast, lungs, heart, 
abdomen, back, lymph nodes, extremities, and nervous system).
The directed physical examination should be based on the subject’s condition and 
circumstances, at the investigator’s discretion. The directed physical examination should note 
any changes in the subject’s condition (body systems) since the last examination and does not 
preclude examination of any of the body systems as clinically indicated.
Changes in physical examination findings (abnormalities) that the investigator considers 
clinically significant will be recorded on the medical history eCRF page if observed prior to 
administration of the first dose of IV study treatment. Changes in physical examination 
findings (abnormalities) that the investigator considers clinically significant must be recorded 
as AEs if observed after the start of the first dose of IV study treatment.
Assessment of Clinical Signs and Symptoms of Complicated Urinary Tract 
Infection, Including Pyelonephritis
The clinical signs and symptoms of cUTI, including pyelonephritis (see Section 5.1.2 - Subject 
Inclusion Criteria, Criterion 7) will be evaluated at the visits specified in Section 6.0 – Trial 
Flow Chart. The signs and symptoms of cUTI will be assessed at Screening by clinical 
examination. Specific findings (eg, fever, failure to thrive, recent weight loss, irritability, poor 
feeding, lack of normal level of activity, abdominal pain/tenderness, vomiting, dysuria, urinary 
urgency, etc.) will be assessed and noted as absent, present, or not able to assess/not done.
At visits after Screening, the investigator will assess each observed sign or symptom according 
to the categories above. The clinical signs and symptoms of cUTI are not considered AEs, 
unless a sign or symptom qualifies as an SAE.
Adverse Event Monitoring
Assessment and recording of AEs is described in Section 7.2 – Assessing and Recording 
Adverse Events. All SAEs will be followed until resolution, stabilization, withdrawal of 
consent, or death.
Assessment of Clinical Outcome
At the visits indicated in Section 6.0 – Trial Flow Chart, the investigator or qualified designee 
will assign the subject’s clinical outcome to a category (cure, partial improvement, failure, or 
indeterminate) as described in Section 4.2.3.2 – Rationale for Efficacy Endpoints.
 
 
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Assessment of Microbiological Outcome
All microbiological outcomes will be assessed by the Sponsor based on culture results as 
eradication, persistence, or indeterminate, as defined in Section 4.2.3.2 – Rationale for Efficacy 
Endpoints. Investigators are not responsible for assessment of microbiological outcomes.
Assessment of Composite Clinical and Microbiological Outcome
Composite response (clinical success and microbiological eradication) will be categorized as 
cure, failure, or indeterminate, as defined in Section 4.2.3.2 – Rationale for Efficacy Endpoints.
Investigators are not responsible for assessment of composite clinical and microbiological 
outcomes.
Assessment of Emergent Infection
Emergent pathogens (ie, those isolated after Screening) will be assessed by the Sponsor for the 
outcome of superinfection or new infection, as defined in Section 4.2.3.2 – Rationale for 
Efficacy Endpoints. Investigators are not responsible for assessment of emergent infections.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory procedure/assessment data will be recorded in source documents 
and the appropriate location in the eCRF.
The total amount of blood to be drawn/collected over the course of the trial (from screening to 
the last trial evaluation), including approximate blood volumes drawn/collected by visit per 
subject can be found in Appendix 12.2 – Approximate Blood Volumes Drawn/Collected by 
Trial Visit.
Laboratory Safety Evaluations (Hematology and Chemistry)
At the visits specified in Section 6.0 – Trial Flow Chart, blood samples will be obtained for
the indicated laboratory tests (hematology and chemistry; Table 9). See Appendix 12.2 –
Approximate Blood Volumes Drawn/Collected by Trial Visit for the maximum expected blood 
volumes needed for laboratory tests.
At Screening, blood samples will be collected for laboratory safety evaluations to determine 
trial eligibility, as follows: serum creatinine, ANC, AST, ALT, and total bilirubin. These
laboratory safety evaluations for trial eligibility will be performed by the local laboratory. A 
blood sample will also be collected at Screening for the direct Coombs test, which the site will 
send to the central laboratory for testing.
Blood samples collected for laboratory safety evaluations after the Screening Visit will be 
tested by the local laboratory. At the EOIV Visit, a blood sample will be collected for the direct 
Coombs test, which the site will send to the central laboratory for testing. The blood sample 
for direct Coombs test may be drawn on Day 3 (with the blood samples for chemistry and 
hematology safety evaluations) if the EOIV Visit is planned for Day 4.
 
 
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Blood samples for laboratory safety evaluations will be collected without regard to meals or 
study treatment.
Table 9
Laboratory Safety Evaluations
Hematology
Chemistry
Hematocrit
Albumin
Hemoglobin
Alkaline phosphatase
Platelets
ALT
Leukocytes (total and differential)
AST
Direct Coombs test
Bicarbonate
Calcium
Chloride
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total bilirubin
Direct bilirubin, if total bilirubin is >ULN
Total protein
BUN
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; ULN = 
upper limit of normal
NOTE: All laboratory safety evaluations will be performed by the local laboratory, except the direct Coombs 
test; sites will send blood samples for the direct Coombs test to the central laboratory for testing.
Urine Microscopy
Urine will be collected for microscopy, including WBC count to assess pyuria as specified in 
Section 6.0 – Trial Flow Chart. Urine microscopy will be performed by the local laboratory.
Pyuria is defined as dipstick analysis positive for leukocyte esterase, OR:

If ≥1 year of age: WBC count >10 cells/µL in unspun urine or ≥10 cells/high power 
field in spun urine

If <1 year of age: WBC count >5 cells/µL in unspun urine or ≥5 cells/high power field 
in spun urine
Urine may be collected by suprapubic aspiration, clean intermittent urethral catheterization, 
indwelling urethral catheter, or mid-stream clean catch. Urine specimens obtained from Foley 
bags are not allowed for the study-qualifying baseline urine culture specimen.
The use of sterile urine collection bags is allowed for young children who are unable to provide 
mid-stream clean catch urine specimens at the EOIV, EOT, and TOC Visits. However, urine 
microscopy must be performed to detect pyuria in the urine sample; if pyuria is not present (as 
 
 
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defined per inclusion criteria #6), then any bacterial growth may be considered a contaminant 
rather than a true superinfection or new infection.
Pregnancy Testing
Pregnancy testing will be performed by the local laboratory on female subjects of child-bearing 
potential at the visits specified in Section 6.0 – Trial Flow Chart. Prior to randomization, the 
investigator will ensure serum pregnancy tests are negative in female subjects of child-bearing 
potential.
A urine pregnancy test instead of a serum pregnancy test may be done at the TOC Visit by the 
local laboratory, if deemed clinically appropriate by the investigator.
Assessment of Creatinine Clearance
Blood samples for serum creatinine will be obtained as indicated in Section 6.0 – Trial Flow 
Chart and evaluated by the local laboratory. The subject’s CrCL will be estimated using the 
serum creatinine value, height, and the revised Schwartz equation [24], as follows:
Glomerular filtration rate (GFR) (mL/min per 1.73 m2) = 0.413 * H/Scr, where

GFR = glomerular filtration rate (mL/min per 1.73 m2)

H = height (cm)

Scr = serum creatinine (mg/dL)
For subjects with unstable renal function (CrCL is close to 50 mL/min/1.73 m2) while receiving 
IV study treatment, obtain serum creatinine value and monitor CrCL at least daily. Subjects 
with CrCL <50 mL/min/1.73 m2 must be discontinued from the IV study treatment.
Urine Samples for Culture
A baseline urine sample for culture must be obtained within 48 hours before the start of 
administration of the first dose of study treatment and preferably prior to administration of any 
potentially therapeutic antibiotics. If more than 1 appropriately collected urine culture sample
is obtained before the initiation of study treatment, the specimen obtained closest to the time
of the administration of the first dose of study treatment will be considered the Screening
specimen.
Urine specimens are to be obtained by suprapubic aspiration, clean intermittent urethral 
catheterization, indwelling urethral catheter, or mid-stream clean catch. Urine specimens
obtained from Foley bags are not allowed for the study-qualifying baseline urine culture 
specimen.
The use of sterile urine collection bags is allowed for young children who are unable to provide 
mid-stream clean catch urine specimens at the EOIV, EOT, and TOC Visits. However, urine 
microscopy must be performed to detect pyuria in the urine sample; if pyuria is not present (as 
defined per inclusion criteria #6), then any bacterial growth may be considered a contaminant 
rather than a true superinfection or new infection.
 
 
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A baseline study-qualifying urine culture must contain 1 and not more than 2 gram-negative 
bacterial isolates at ≥105 CFU/mL each, as follows:

For non-catheterized subjects, if more than 2 bacterial isolates are identified from a 
single urine specimen, the culture will be suspected contaminated unless a pathogen of 
≥105 CFU/mL is also isolated from the blood culture at the Screening Visit. 

For catheterized subjects, if more than 1 bacterial isolate is identified from a single 
urine specimen, the culture will be suspected contaminated unless a pathogen of 
≥105 CFU/mL is also isolated from the blood culture at the Screening Visit. 

The full list of appropriate gram-negative uropathogens will be provided in a laboratory 
manual. The following pathogens will not be considered causative pathogens of cUTI 
in this trial:
o
Coagulase-negative Staphylococci
o
Non-Group D Streptococci
NOTE: The Lancefield category [47] is shown below as reference:

Group A: Streptococcus pyogenes

Group B: S. agalactiae

Group C and G: S. equi, S. canis
Baseline urine culture results (sample obtained at Screening) will be verified at the first 
Clinical Assessment Visit at which results are available. Subjects who are not documented as 
having ≥105 CFU/mL of an appropriate gram-negative uropathogen cultured from a screening 
urine specimen must discontinue from the trial immediately upon receipt of the culture result. 
At the time study treatment is discontinued, all EOIV/EOT Visit procedures must be completed 
and recorded. Subjects should return to the trial site for the TOC Visit 5 to 9 days after 
administration of the last dose of study treatment and return or be contacted for the LFU Visit
28 to 35 days after administration of the last dose of study treatment to complete safety 
assessments. Last Follow-up Visit procedures must be completed 28 to 35 days after the final 
dose of study treatment.
Urine cultures, isolation of uropathogen(s), initial identification of pathogen(s), susceptibility 
testing, and bacterial counts in urine will be conducted by the local laboratory. The results of 
urine cultures, initial identification of pathogen(s), and bacterial counts at the local laboratory 
will be recorded. The sites will also ship the isolated pathogen(s) to the central microbiology 
laboratory for re-identification of uropathogen(s) and MIC testing. Further details of the 
procedures to be followed for sample collection, storage, and shipment will be provided in a 
laboratory manual.
Blood Samples for Culture
Blood samples are collected for culture as specified in Section 6.0 – Trial Flow Chart. Blood 
samples for culture should be collected if signs of sepsis appear at any time during the study. 
Further details of the procedures to be followed for sample collection, storage, and shipment 
will be provided in a laboratory manual.
 
 
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Blood samples for culture will be obtained for all subjects at Screening if clinically indicated. 
Culture of the blood specimen, isolation of pathogen(s), initial identification of pathogen(s), 
and susceptibility testing will be conducted by the local laboratory and recorded. The sites will
ship the isolated pathogen(s) to the central microbiology laboratory for re-identification and 
MIC testing. Further details of the procedures to be followed for sample collection, storage, 
and shipment will be provided in a laboratory manual.
Pharmacokinetic Evaluations
Whole blood to obtain plasma samples will be collected for population PK analysis of 
ceftolozane and tazobactam as specified in Section 6.0 – Trial Flow Chart. These samples may 
also be used in the assessment of the clinical relationship between ceftolozane and tazobactam 
plasma concentrations and efficacy, as appropriate.
Blood samples for ceftolozane, tazobactam, and tazobactam M1 concentration assays and 
plasma PK parameters (for ceftolozane and tazobactam) will be collected from all subjects 
over one 8-hour dosing period on Day 3 of the treatment period after administration of at least 
6 doses of IV study treatment. These blood samples will be collected at the following times: 
At the end of infusion (collected within 10 minutes after the end of total dose administration); 
between 2.5 and 3.5 h post start of infusion; and between 5.0 and 6.0 hours post start of infusion 
but prior to the start of the next dose of study treatment.
Pharmacokinetic sample collection may occur on Day 4 if the last dosing period of Day 3 is 
selected for PK sample collection. Additionally, if sampling on Day 3 is logistically difficult, 
sampling may be performed at comparable time points after Day 3 in subjects who are 
continuing to receive IV study treatment.
Plasma will be separated from blood and sent to the central laboratory for PK testing. Details 
of the procedures for collection, processing, storage, and shipment of PK samples from blood 
(plasma) will be provided separately in a laboratory manual. Actual whole blood sample 
collection dates and times must be recorded on the appropriate eCRF.
Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue study treatment prior to completion of the study treatment regimen
(IV only or IV + oral) should be encouraged to continue to be followed for all remaining study 
visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the EOIV or EOT Visit, as described in Section 7.1.5.9 – Subjects Who 
Prematurely Discontinue From Study Treatment or the Trial, should be performed at the time 
of discontinuation.  Any adverse events which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 7.2 - Assessing and Recording Adverse Events .
 
 
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Lost to Follow-up
If a subject fails to return to the clinic for a required trial visit and/or if the site is unable to 
contact the subject, the following procedures will be performed:

The site must attempt to contact the subject and reschedule the missed visit. If the 
subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the 
subject at each missed visit (eg, phone calls and/or a certified letter to the subject’s 
last known mailing address or locally equivalent methods). These contact attempts 
should be documented in the subject’s medical record.
NOTE: A subject is not considered lost to follow-up until the last scheduled visit for the 
individual subject. The amount of missing data for the subject will be managed via the 
prespecified data handling and analysis guidelines.
Unblinded Pharmacist
Subjects will receive the IV study treatment, following preparation by an unblinded pharmacist
(Section 5.2.6 – Trial Blinding), for a maximum of 14 days. Preparation of study drug by the 
unblinded pharmacist is detailed in the pharmacy manual. Importantly, the unblinded 
pharmacist will be uninvolved in any of the postinfusion evaluations for the subject. All study 
personnel involved with the postinfusion evaluations of safety and efficacy outcomes, 
including the study coordinator(s), investigator, or subinvestigator(s), must have no access to 
the treatment group assignment or the preparation of the study infusion.
Subject Blinding/Unblinding
When the investigator or delegate needs to identify the drug used by a subject and the dosage 
administered in case of emergency e.g., the occurrence of serious adverse events, he/she will 
contact the emergency unblinding call center by telephone and make a request for emergency 
unblinding.  As requested by the investigator or delegate the emergency unblinding call center 
will provide the information to him/her promptly and report unblinding to the Sponsor.  Prior 
to contacting the emergency unblinding call center to request unblinding of a subject’s 
treatment assignment, the investigator or delegate must enter the intensity grade of the adverse 
events observed, the relation to study drug, the reason thereof, etc., in the medical chart etc.
Subjects whose treatment assignment has been unblinded by the investigator/delegate and/or 
non-study treating physician should continue to be monitored in the trial.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call center 
is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
Treatment/Vaccine identification information is to be unmasked ONLY if necessary for the 
welfare of the subject.  Every effort should be made not to unblind the subject unless necessary. 
 
 
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In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date, 
reason and person performing the unblinding) must be documented promptly, and the Sponsor 
Clinical Director notified as soon as possible. Once an emergency unblinding has taken place, 
the principal investigator, site personnel, and Sponsor personnel may be unblinded so that the 
appropriate follow-up medical care can be provided to the participant.
Subjects whose treatment assignment has been unblinded should continue to receive study 
medication.
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Refrigerators or freezers used to store study medication or subject samples/specimens 
that will be sent to the central laboratory
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
Screening assessments are performed within 48 hours prior to the start of administration of the 
first dose of IV study treatment. Assessments (eg, laboratory procedures, vital signs) performed 
prior to providing documented informed consent may be used if collected during the routine 
care of the subject, so long as they were conducted within 48 hours prior to the start of 
administration of the first dose of IV study treatment. Potential subjects are evaluated at the 
Screening Visit to determine if they fulfill the entry requirements in Section 5.1 – Entry 
Criteria. All Screening results must be available prior to randomization. Screening, 
randomization, and first dose of study treatment may all occur on the same day.
Randomization Visit
The Randomization Visit is the date subjects are randomized to treatment arms, and may then 
receive the first dose of double-blind IV study treatment. Screening, randomization, and first 
dose of study treatment may all occur on the same day.
 
 
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Clinical Assessment Visits on Intravenous Study Treatment
Clinical Assessment Visits on IV study treatment occur daily beginning on Day 2 and 
continuing through the last dose of IV study treatment. At these visits, each subject’s 
assessment should be performed at a consistent time each day (eg, every morning), as much as 
possible. Safety laboratory tests and a directed physical examination should be completed on 
Day 3 (±24 hours) and then once weekly while the subject is receiving IV study treatment. 
Subjects cannot go home on IV study treatment.
Blood is collected for PK analyses on Day 3 (after ≥6 doses of IV study treatment). 
Pharmacokinetic sample collection may occur on Day 4 if the last dosing period of Day 3 is 
selected for PK sample collection. Additionally, if sampling on Day 3 is logistically difficult, 
sampling may be performed at comparable time points after Day 3 in subjects who are 
continuing to receive IV study treatment.
End of IV Treatment Visit
The EOIV Visit occurs in all subjects within 24 hours after the last dose of IV study treatment. 
For subjects who receive only IV study treatment and are not switched to oral step-down 
therapy, the EOIV Visit serves as the EOT Visit and these subjects do not have a separate EOT 
Visit. Subjects who are switched to oral step-down therapy will have both an EOIV and EOT 
Visit. If subjects are switched to oral step-down therapy, the oral step-down therapy must be 
initiated <24 hours after stopping IV study treatment. If blood samples for chemistry and 
hematology safety evaluations were collected within 24 hours prior to the EOIV Visit, blood 
samples for these evaluations are not required at this visit.
Clinical Assessment Visit on Oral Step-down Therapy
The Oral Clinical Assessment Visit is completed only for subjects who are switched to oral 
step-down therapy. If subjects are switched to oral step-down therapy, the oral step-down 
therapy must be initiated <24 hours after stopping IV study treatment. This visit should be 
performed once if the subject receives ≥7 days of oral step-down therapy. This visit can be 
performed ±24 hours after 7 days on oral step-down therapy. Subjects who receive <7 days of 
oral step-down therapy will not undergo this visit. Any AE that comes to the attention of the 
investigator before the Oral Clinical Assessment Visit should be recorded at this visit, but any 
SAE must be reported within 24 hours. This visit will be the same whether the subject is still 
in the hospital or has been discharged to home. If the Oral Clinical Assessment Visit and EOT 
Visit are on the same day, only the EOT Visit should be completed.
End of Treatment Visit
The EOT Visit occurs only in subjects who are switched to oral step-down therapy. These 
subjects will have both an EOIV and EOT Visit. This visit will occur within 48 hours after the 
last dose of oral step-down therapy. If blood samples for chemistry and hematology safety 
evaluations were collected within 24 hours prior to the EOT Visit, blood samples for these 
evaluations are not required at this visit.
 
 
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Test of Cure Visit
The TOC Visit occurs in all subjects 5 to 9 days after the final dose of study treatment (IV or 
oral).
Last Follow-up Visit
The LFU Visit occurs in all subjects 28 to 35 days after the final dose of study treatment (IV 
or oral). The LFU Visit will be conducted by telephone; however, if the subject has abnormal 
laboratory values or AEs that require follow-up, an in-person visit is required.
Subjects Who Prematurely Discontinue From Study Treatment or the Trial
Subjects who discontinue from study treatment prior to completion of the study treatment 
regimen (IV only or IV + oral) will continue to be monitored in the trial according to Section 
6.0 – Trial Flow Chart.
For subjects who prematurely withdraw from the trial, see Section 7.1.4.1 –
Withdrawal/Discontinuation and Section 7.1.4.2 – Lost to Follow-up.
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the subject provides documented informed consent but 
before treatment allocation/randomization must be reported by the investigator if they cause 
the subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
 
 
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including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. From the time of treatment allocation/randomization through the last 
trial evaluation (Last Follow-up visit, 28 to 35 days after final dose), all adverse events must 
be reported by the investigator. Such events will be recorded at each examination on the 
Adverse Event case report forms/worksheets.  The reporting timeframe for adverse events 
meeting any serious criteria is described in section 7.2.3.1. The investigator will make every 
attempt to follow all subjects with non-serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this trial, an overdose is any dose greater than 1.5 times higher than the weight-based dosing 
specified for the subject’s age group for ceftolozane/tazobactam and meropenem. For oral step-
down antibiotic therapy, refer to the manufacturer’s label for overdose criteria. Additional 
details are described in the pharmacy manual.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a non-serious adverse event, unless other serious
criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious adverse event using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the investigator 
within 24 hours to the Sponsor either by electronic media or paper. Electronic reporting 
procedures can be found in the EDC data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial.
Pregnancies and lactations of subjects and female partners of male subjects from the time the 
documented informed consent form is provided but before treatment allocation/randomization 
must be reported by the investigator if they cause the subject to be excluded from the trial, or 
are the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.  Pregnancies and 
lactations of subjects and female partners of male subjects that occur from the time of treatment 
 
 
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allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported. All reported pregnancies  must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. 
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 10 for additional details regarding each of the above criteria.
For the time period beginning when the subject provides documented informed consent until 
treatment allocation/randomization, any serious adverse event, or follow-up to a serious 
adverse event, including death due to any cause, that occurs to any subject must be reported 
within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through the last trial 
evaluation (Last Follow-up visit, 28 to 35 days after final dose), any serious adverse event, or 
follow-up to a serious adverse event, including death due to any cause, whether or not related 
to the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. For the time period from the signing of informed consent through treatment 
allocation/randomization, only serious adverse events that either cause the participant to be 
excluded from the trial or are the result of a protocol-specified intervention, must be reported 
within 24 hours to the Sponsor either by electronic media or paper. Electronic reporting 
procedures can be found in the EDC data entry guidelines. Paper reporting procedures can be 
 
 
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found in the Investigator Trial File Binder (or equivalent). All SAEs will be followed until 
resolution, stabilization, withdrawal of consent, or death.
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with SAEs must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the subject provides documented informed consent until 
treatment allocation/randomization, any ECI, or follow up to an ECI, that occurs to any 
subject must be reported within 24 hours to the Sponsor if it causes the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.
For the time period beginning at treatment allocation/randomization through the last trial 
evaluation (Last Follow-up visit, 28 to 35 days after final dose), any ECI, or follow up to an 
ECI, whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines.  Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
2. An overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 10. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 10 for instructions in evaluating adverse events.
 
 
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Table 10
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.  (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Overdose, although not serious per ICH definition, whether accidental or intentional, with or without an accompanying adverse event/serious adverse event, is 
reportable to the Sponsor within 24 hours to meet certain local requirements.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event? The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor's product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
Executive Oversight Committee
The EOC comprises members of Sponsor Senior Management. The EOC will receive and 
decide upon any recommendations made by the DMC regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this trial.  The voting members of the committee are external to 
the Sponsor.  The members of the DMC must not be involved with the trial in any other way 
(e.g., they cannot be trial investigators) and must have no competing interests that could affect 
their roles with respect to the trial.
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial. Also, the DMC will review interim trial
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the trial. Changes to 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a supplemental Statistical Analysis Plan (sSAP) and referenced in the Clinical 
Study Report (CSR) for the trial. For any analyses in the sSAP and protocol, the sSAP will 
supersede those described in the protocol. Post hoc exploratory analyses will be detailed in the 
CSR.
Key elements of the Statistical Analysis Plan are summarized in Section 8.1. The 
comprehensive plan is provided in Sections 8.2 through 8.12.
 
 
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Statistical Analysis Plan Summary
Trial Design Overview
A Phase 2 randomized, active comparator-controlled, multicenter, 
double-blind, clinical trial to study the safety and efficacy of 
ceftolozane/tazobactam (MK-7625A) versus meropenem in pediatric 
subjects with complicated urinary tract infections (cUTIs), including 
pyelonephritis.
Treatment Assignment
Approximately 240 pediatric subjects (combined across MK-7625A-
034 and MK-7625A-035) in 5 age groups will be enrolled and 
randomized in a 3:1 ratio to receive IV ceftolozane/tazobactam or IV 
meropenem, respectively. The total duration of study treatment will be 
a minimum of 7 days to a maximum of 14 days. Randomization will be 
stratified by age group. See Table 7 for target enrollments and IV 
dosage regimens for each age group.
Analysis Populations
Safety: All Subjects as Treated (ASaT) Population
Pharmacokinetics: PK Population
Efficacy: Microbiological Modified Intent-to-Treat (mMITT), 
Microbiologically Evaluable (ME), and Clinically Evaluable (CE) 
Populations
Primary Endpoints
The primary safety parameters will include the following safety 
evaluations:

AEs

Clinical laboratory tests

Vital signs 
Key Secondary Endpoints

Clinical success at the EOT and TOC Visits

Per-subject microbiological eradication at the EOT and TOC Visits
Statistical Methods for Key 
Efficacy/PK Analyses
A 2-sided 95% confidence interval (CI) based on the M&N method [48]
stratified by age group will be provided to evaluate the treatment 
differences for clinical success at the EOT and TOC Visits and per-
subject microbiological eradication at the EOT and TOC Visits.
There will be no efficacy hypothesis testing in this estimation trial.
Statistical Methods for Key 
Safety Analyses
Tier 2 endpoints include AEs of elevated laboratory values; the 
percentage of subjects with any AE, any SAE, and any treatment-
related AE, any serious and study treatment-related AE; the percentage 
of subjects who discontinue due to an AE; and AEs (specific preferred 
terms), system organ classes, or values outside of the local laboratory’s 
reference range with frequency ≥6 subjects in the experimental 
treatment arm and/or ≥2 subjects in the comparator treatment arm. The 
95% CIs will be provided for between-treatment differences in the 
percentage of subjects with events; these analyses will be performed 
using the unstratified M&N method [48], an unconditional, asymptotic 
method.
Changes in laboratory and vital sign values from baseline will be 
summarized as Tier 3 events using descriptive statistics.
Interim Analyses
No interim analyses for efficacy are planned for this trial. However, an 
external DMC will convene to review combined safety data from the 
present trial and the companion Phase 2 trial in pediatric subjects with 
cIAI (MK-7625A-035). Additional details are available in the external 
DMC charter.
 
 
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Multiplicity
There will be no adjustment for multiplicity in this estimation trial.
Sample Size and Power 
Approximately 240 subjects (combined across MK-7625A-034 and
MK-7625A-035) will be enrolled, with approximately 180 subjects in 
the ceftolozane/tazobactam arm and approximately 60 subjects in the 
meropenem arm. The estimated differences and 95% CIs for event rate 
under various scenarios for the combined trials are presented in
Table 15. For example, if the overall event rate is 10% across both 
treatment arms (18 out of 180 and 6 out of 60 subjects, respectively), 
the 95% CI for the between-treatment difference is -13.4, 8.5.
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this trial will be the responsibility of the 
Sponsor’s Clinical Biostatistics department.
This trial will be conducted as a double-blind trial under in-house blinding procedures. The 
official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented via an IVRS/IWRS.
The interim review of the safety data will be performed by the external DMC (Section 7.3.2 –
Data Monitoring Committee). Treatment level results will be provided by the external 
unblinded statistician to the external DMC. Limited additional Sponsor personnel may be 
unblinded to the treatment level results of the safety analyses, if required, in order to act on the 
recommendations of the external DMC. The extent to which individuals are unblinded with 
respect to results of safety review will be documented by the unblinded statistician.
The external DMC will serve as the primary reviewer of the safety results from this study with 
respect to the safety reviews and will make recommendations for discontinuation of or 
modifications to the study to the EOC of the Sponsor (Section 7.3.1 – Executive Oversight 
Committee). If the external DMC recommends modifications to the design of the protocol or 
discontinuation of the study, the EOC (internal to the Sponsor) may be unblinded to results at 
the treatment level in order to act on these recommendations. Additional logistic details will 
be provided in the external DMC charter.
Prior to final study unblinding, the unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol violators, or data validation efforts after the interim safety review(s).
Pharmacokinetic data will be unblinded early for the purpose of preparing a population PK 
model. A separate Modeling and Simulation Plan authored by the department of Quantitative 
Pharmacology and Pharmacometrics will describe the modeling work to be performed. A small 
team, who are separate from the protocol team, will be unblinded for the purpose of preparing 
the population PK model. Efficacy and safety data will not be unblinded. Interim data or results 
will not be shared with the protocol team before study unblinding.
 
 
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Hypotheses/Estimation
Objectives of the trial are stated in Section 3.0 – Objectives & Hypothesis(es). No efficacy or 
safety hypothesis testing will be conducted in this estimation trial.
Analysis Endpoints
Safety and efficacy endpoints that will be evaluated for between-treatment differences are 
listed below, followed by the descriptions of the derivations of selected endpoints.
Safety Endpoints
In order to evaluate the safety and tolerability of ceftolozane/tazobactam, the following safety 
endpoints will be summarized based on the ASaT population: AEs, laboratory data, and vital 
signs.
An initial description of safety measures is provided in Section 4.2.3.1 – Rationale for Safety 
Endpoints and Events of Clinical Interest (ECIs) are defined in Section 7.2.3.2 – ECIs. The 
proportion of subjects who experience AEs of elevated laboratory values that are reported as 
ECIs during the study treatment period will be estimated.
Adverse Events
The proportion of subjects with AEs of the following types at any time from the first dose of 
study treatment to the last trial evaluation will be investigated: (1) Any AE, (2) any SAE, (3) 
any drug-related AE, (4) any serious and drug-related AE, and (5) any AE leading to study 
treatment discontinuation.
Laboratory Data
For the summaries of laboratory tests, subjects must have both a baseline and post-
randomization on-treatment measurement to be included. Subjects’ laboratory values (based 
on their most abnormal laboratory test values, in the direction of interest, while on study 
treatment) will be classified as to whether or not they fall outside of the local laboratory’s 
reference range and are worse in grade (ie, more abnormal in the direction of interest) than at 
baseline.
Summaries of laboratory changes from baseline to the EOIV, EOT, and TOC Visits, and from 
baseline to the LFU Visit, as data permit, will be presented.
The number and percentage of subjects in each treatment arm with an elevated AST or ALT
level (>3 × ULN, >5 × ULN, and >10 × ULN) and bilirubin level (>1.5 × ULN and >2 × ULN) 
will be presented by trial visit (as specified in Section 6.0 - Trial Flow Chart) for the ASaT 
population.
A listing of subjects who meet the following predetermined laboratory criteria will also be 
provided for the ASaT population, including 1) ALT or AST >3 × ULN, alkaline phosphatase 
 
 
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≤2 × ULN, and total bilirubin >1.5 × ULN and 2) ALT or AST >3 × ULN, alkaline phosphatase 
≤2 × ULN and total bilirubin >2 × ULN.
Vital Signs
Vital sign parameters will include heart rate (beats per minute), respiratory rate (breaths per 
minute), systolic and diastolic blood pressure (BP) in mm mercury (Hg), and temperature in 
degrees Celsius (°C) by treatment group and trial day/visit.
Other safety parameters include physical examinations and standard laboratory safety tests at 
time points specified in Section 6.0 – Trial Flow Chart.
Efficacy Endpoints
There are no primary efficacy endpoints for this study; the primary endpoints are safety 
parameters (Section 8.4.1 – Safety Endpoints).
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

Clinical success rate at the EOT and TOC Visits, defined as the proportion of subjects 
in the analysis population who have a clinical response of cure.

Per-subject microbiological eradication rate at the EOT and TOC Visits, defined as 
the proportion of subjects in the analysis population who have an overall outcome of 
microbiological eradication.
NOTE: For subjects who receive IV study treatment only (without optional oral step-down 
therapy), a separate assessment does not need to be performed at the EOT Visit; the EOIV 
Visit will serve as the EOT Visit.
Clinical outcome categories are defined in Table 3 and microbiological outcome categories are 
defined in Table 4 in Section 4.2.3.2 – Rationale for Efficacy Endpoints.
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are as follows:

Clinical success rate at the EOIV Visit, defined as the proportion of subjects in the 
analysis population who have a clinical response of cure or partial improvement.
NOTE: At EOIV, clinical success is defined as cure or partial improvement. At EOT 
and TOC, clinical success is defined as cure. The definition for clinical success at the 
EOIV Visit includes partial improvement to accommodate those subjects with partial 
improvement who are switched to oral step-down therapy at this time point. 

Per-subject microbiological eradication rate at the EOIV Visit.
 
 
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
Per-pathogen microbiological eradication rate at the EOIV, EOT, and TOC Visits, 
defined as the proportion of pathogens in the analysis population that have an 
outcome of microbiological eradication.

Composite success (clinical success and per-subject microbiological eradication) rate 
at the EOIV, EOT, and TOC Visits.
NOTE: For subjects who receive IV study treatment only (without optional oral step-down 
therapy), a separate assessment does not need to be performed at the EOT Visit; the EOIV
Visit will serve as the EOT Visit.
Clinical outcome categories are defined in Table 3, microbiological outcome categories are 
defined in Table 4, and composite clinical and microbiological outcome categories are defined 
in Table 5 in Section 4.2.3.2 – Rationale for Efficacy Endpoints.
The percentage of subjects with superinfection or new infection will also be estimated.
Emergent infection categories are defined in Table 6 in Section 4.2.3.2 – Rationale for Efficacy 
Endpoints.
Pharmacokinetic Endpoints
Plasma concentration for ceftolozane, tazobactam, and tazobactam M1 will be determined. The 
data will be used to update the existing ceftolozane and tazobactam pediatric population PK 
models, which will be used to perform simulations to evaluate target attainment at suitable 
doses.
The PK target that best correlates with efficacy is % fT>MIC and % fT>Ct for ceftolozane and 
tazobactam, respectively. Therefore, in addition to plasma exposure (AUC0-8 and Cmax), % 
fT>MIC and % fT>Ct will be derived for ceftolozane and tazobactam, respectively.
Plasma concentrations for tazobactam M1 will be reported separately.
Analysis Populations
Safety Analysis Populations
The ASaT population will be used for the analysis of safety data in this trial. The ASaT 
population will consist of all randomized subjects who receive any amount of study treatment. 
Subjects will be included in the treatment arm corresponding to the IV study treatment they 
actually received, irrespective of the treatment to which they were randomized. If any subject 
receives study treatment from both treatment arms, he or she will be assigned to the treatment 
arm from which more study treatment was received.
Efficacy Analysis Populations
The efficacy analysis populations are defined in Table 11. Additional details about evaluability 
criteria for each efficacy analysis population will be provided in an evaluability guideline 
document.
 
 
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Table 11
Efficacy Analysis Populations
Populationa
Definitiona
Microbiological Modified 
Intent-to-Treat (mMITT)
The mMITT population will be the subset of randomized subjects who receive 
any amount of study treatment and have at least 1 acceptable causative 
uropathogen identified from a study-qualifying baseline urine culture. Subjects 
will be categorized based on the IV study treatment they were randomized to, 
irrespective of what they actually received.
Clinically Evaluable (CE)
The CE population will be the subset of subjects in the mMITT population 
who adhere to trial procedures. An interpretable urine culture is not required at 
the visit of interest. All subjects must have an evaluable clinical outcome at the 
visit of interest; subjects with an indeterminate clinical outcome are excluded 
from the CE population.
Microbiologically 
Evaluable (ME)
The ME population will be the subset of subjects in the CE population who 
have an interpretable urine culture at the visit of interest.
a
Additional details about evaluability criteria for each efficacy analysis population will be provided in an 
evaluability guideline document.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6 - Statistical Methods.
Statistical Methods
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs measurements.
The analysis of safety results for this trial will follow a tiered approach (Table 12). The tiers 
differ with respect to the analyses that will be performed. Based upon review of adult and 
pediatric trial safety data, no Tier 1 AEs of interest have been identified for this trial. Therefore, 
all safety parameters will be considered Tier 2 or Tier 3. Tier 2 parameters will be assessed via 
point estimates with 95% CIs provided for between-group comparisons; only point estimates 
by treatment arm are provided for Tier 3 safety parameters.
Tier 2 endpoints for this trial include the percentage of subjects with AEs of elevated laboratory 
values, any AE, any treatment-related AE, any SAE, any AE that is both treatment-related and 
serious, and subjects who discontinued due to an AE. The 95% CIs will be provided for 
between-treatment differences in the percentage of subjects with events; these analyses will be 
performed using the unstratified M&N method [48], an unconditional, asymptotic method.
Adverse events (specific preferred terms), system organ classes, or values outside of the local 
laboratory’s reference range with at least 6 events in the experimental treatment arm and/or 
2 events in the comparator treatment arm will be classified as belonging to Tier 2. Adverse 
events (specific preferred terms), system organ classes, or values outside of the local 
laboratory’s reference range with frequencies less than these criteria in both treatment arms 
combined will be classified as belonging to Tier 3.
 
 
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These thresholds were chosen because the 95% CI for the between-group difference in 
percentage will include zero when these thresholds are not met and thus would add little to the 
interpretation of potentially meaningful differences.
Because many 95% CIs may be provided without adjustment for multiplicity, the CIs should 
be regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of between-group differences in AEs.
Continuous measures such as changes from baseline in laboratory parameter and vital sign 
values will be considered Tier 3 safety parameters. Summary statistics for baseline, on-
treatment, and change from baseline values will be provided by treatment arm in table format. 
In addition, summary statistics for both treatments will be provided. Safety summaries by 
treatment methods (IV study treatment or oral step-down therapy) and age groups will also be 
generated.
Missing safety parameters will be handled using the data as observed (DAO) approach, that is, 
any subject with a missing value will be excluded from the analysis. Change from baseline 
summaries require a baseline value. If a baseline value is missing, the latest pretreatment value 
will be used instead. If no pretreatment result is available, that subject will not be included in 
the summary. The safety summarization of results will be presented by treatment arm unless 
otherwise specified. Additional subgroup safety analysis summaries for the dosed subjects may 
be requested as needed.
 
 
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Table 12
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
AEs of elevated laboratory values 
X
X
Any AE
X
X
Any SAE
X
X
Any treatment-related AE
X
X
Any serious and treatment-related AE
X
X
Discontinuation from trial treatment due to AE
X
X
AEs (specific preferred terms), system organ classes, 
or values outside of the local laboratory’s reference 
range with frequency ≥6 subjects in the experimental 
treatment arm and/or ≥2 subjects in the comparator 
treatment arm
X
X
Tier 3
AEs (specific preferred terms), system organ classes, 
or values outside of the local laboratory’s reference 
range with frequency <6 subjects in the experimental 
treatment arm and frequency <2 subjects in the 
comparator treatment arm
X
Change from baseline in laboratory parameter and 
vital sign values
X
AE = adverse event; CI = confidence interval; SAE = serious adverse event
Statistical Methods for Efficacy Analyses
For clinical and microbiological responses, missing data will be primarily handled with a 
treatment failure approach for the mMITT population and a DAO approach for the ME and CE 
populations (Table 13), with the following definitions:

For the analysis of clinical response, microbiological response, and composite clinical 
and microbiological response in the mMITT population, the subjects with a missing 
clinical response or microbiological response (eg, indeterminate) will be considered
treatment failures.

For the analyses in the ME or CE population, the subjects with a missing clinical 
response or microbiological response (eg, indeterminate) will be excluded from the 
population.

A missing per-pathogen microbiological outcome at the TOC Visit will be considered 
an indeterminate outcome unless the per-pathogen microbiological outcome at the 
EOIV or EOT Visit is persistence. A per-pathogen microbiological outcome of 
persistence at the EOIV or EOT Visit will be carried forward to the TOC Visit.
 
 
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
A missing clinical outcome at the TOC Visit will be considered an indeterminate 
outcome unless the clinical outcome at the EOIV or EOT Visit is failure. A clinical 
response of failure at the EOIV or EOT Visit will be carried forward to the TOC 
Visit.
The M&N statistical method [48] with data stratified by age group will be used to make 
between-group comparisons for binary outcomes (Table 14), but no tests of hypotheses are 
planned in this estimation trial.
Table 13
Analysis Strategy for Efficacy Variables
Endpoint/Variable a
(Description, Timepoint)
Primary (P) or 
Supportive (S) 
Approach
Analysis 
Population
Missing Data Approach
Secondary Endpoints
Clinical success rate at the EOT and 
TOC Visits
P
mMITT
Treatment Failure
S
CE
Data As Observed
Per-subject microbiological eradication
rate at the EOT and TOC Visits
P
mMITT
Treatment Failure
S
ME
Data As Observed
Exploratory Endpoints
Clinical success rate at the EOIV Visit
P
mMITT
Treatment Failure
S
CE
Data As Observed
Per-subject microbiological eradication
rate at the EOIV Visit
P
mMITT
Treatment Failure
S
ME
Data As Observed
Per-pathogen microbiological 
eradication rate at the EOIV, EOT, and 
TOC Visits
P
mMITT
Treatment Failure
S
ME
Data As Observed
Composite response (clinical success
and per-subject microbiological
eradication) rate at the EOIV, EOT, 
and TOC Visits
P
mMITT
Treatment Failure
S
ME
Data As Observed
CE = clinically evaluable; EOIV = End of IV Treatment; EOT = End of Treatment; LFU = Last Follow-up; 
ME = Microbiologically Evaluable; mMITT = microbiological Modified Intent-to-Treat; TOC = Test of 
Cure
a
The Miettinen and Nurimen statistical method [48] will be used for all analyses and will include 
stratification by age group.
NOTE: For subjects who receive IV study treatment only (without optional oral step-down therapy), a 
separate assessment does not need to be performed at the EOT Visit; the EOIV Visit will serve as the EOT 
Visit.
 
 
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Table 14
Estimated Two-sided 95% Confidence Intervals Based on Different Assumed 
Observed Rates of Efficacy Endpoints
Same Observed Clinical 
Success or Per-subject 
Microbiological Response 
Rate Across Both Arms
Ceftolozane/tazobactam
(n=90)
Meropenem
(n=30)
Estimate (95% CI)
70%
63 (70.0%)
21 (70.0%)
0.00 (-17.20, 20.08)
80%
72 (80.0%)
24 (80.0%)
0.00 (-14.50, 18.88)
90%
81 (90.0%)
27 (90.0%)
0.00 (-10.60, 16.46)
CI = confidence interval
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Analyses of Baseline Characteristics and Demographics
No statistical hypothesis tests will be performed on demographic and baseline characteristics. 
The number and percentage of subjects screened, randomized/allocated, the primary reasons 
for screening failure, and the primary reasons for discontinuation will be displayed. 
Demographic variables (as follows), baseline characteristics, primary diagnosis, prior and 
concomitant therapies, and medical history will be summarized by treatment using descriptive 
statistics for continuous or categorical variables, as appropriate. Summaries of baseline 
pathogens and signs and symptoms will also be provided.
Demographic variables include but are not limited to the following: Age, sex, race, body 
weight, body mass index (BMI), and geographic region of enrollment.
Baseline characteristics include but are not limited to the following:

CrCL group (<50 mL/min, ≥50 to <80 mL/min, ≥80 mL/min)

Baseline diagnosis (pyelonephritis or cLUTI)

Baseline clinical signs and symptoms for cUTI

Complicating factor(s) for cLUTI

Indwelling catheter (yes, no)

Number of uropathogens present at baseline (1, 2, or ≥3)

Uropathogens group (gram-negative, gram-positive, Others)

Pretreatment with systemic gram-negative antibacterial agents (yes, no)

Presence of bacteremia at baseline (yes, no)

ESBL status of Enterobacteriaceae (ESBL, non-ESBL)

AmpC overexpression status
In addition, for randomized subjects, baseline characteristics will be presented by age category 
and treatment arm.
 
 
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Population Pharmacokinetic Analyses
Based on PK data obtained within this study, a separate population PK analysis will be 
performed for ceftolozane and tazobactam. The prospective details of this analysis will be 
specified in a separate population PK analysis plan and the results will be included in a separate 
report.
Interim Analyses
No interim analyses for efficacy are planned for this trial. However, an external DMC will 
convene to review combined safety data from the present trial and the companion Phase 2 trial 
in pediatric subjects with cIAI (MK-7625A-035). Additional details are available in the 
external DMC charter.
Multiplicity
There will be no multiplicity adjustments in the analyses of this estimation trial.
Sample Size and Power Calculations
This is an estimation trial; no formal statistical testing will be performed for the efficacy or 
safety endpoints. In this trial, approximately 240 subjects (combined across MK-7625A-034 
and MK-7625A-035) will be enrolled with an expected 180 subjects in the 
ceftolozane/tazobactam treatment arm and an expected 60 subjects in the meropenem treatment 
arm. With a sample size of 180 ceftolozane/tazobactam-treated subjects in both this trial and 
the tandem cIAI trial (MK-7625A-035) (Section 4.2.1.1 – Rationale for Sample Size), AEs 
with an underlying true incidence of at least 2% in the treatment arm are anticipated to occur 
with a probability of at least 97%.
The primary objective of this trial is assessment of the accumulated safety data. Trial-specific 
safety assessments are described in Section 8.6.1– Statistical Methods for Safety Analyses. 
However, safety data will be combined across MK-7625A-034 and MK-7625A-035. Table 15
shows estimated treatment differences and associated 2-sided 95% CIs for events under 
varying assumptions of the observed number of subjects having a certain event combined 
across trials. These calculations are based on the unstratified M&N method [48].
 
 
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Table 15
Estimated Treatment Differences and Two-sided 95% Confidence Intervals
Same Expected Event Rate 
Across Both Treatment 
Groups
Ceftolozane/tazobactam
(n=180)
Meropenem
(n=60)
Estimate (95% CI)
2%
4 (2.2%)
2 (3.3%)
-1.1 (-9.30, 3.05)
4%
8 (4.4%)
4 (6.7%)
-2.2 (-1.18, 3.57)
10%
18 (10.0%)
6 (10.0%)
0.0 (-10.80, 7.64)
15%
28 (15.6%)
10 (16.7%)
-1.1 (-13.42, 8.53)
CI = confidence interval
NOTE: Given the same expected event rate across both treatment groups, treatment difference estimates are 
not always zero given the discrete nature of events. The number of events within each treatment group is 
selected based on the minimum number of events required to match or exceed the expected event rate across 
both groups.
Subgroup Analyses
To assess the consistency of clinical and microbiological response at the EOT and TOC Visits, 
the response rates with 95% CIs will be estimated for each treatment arm within each category 
listed below.

Age category (birth to <3 months, 3 months to <2 years, 2 years to <6 years, 6 years 
to <12 years, 12 years to <18 years)

Sex (male, female)

Region of enrollment

Baseline diagnosis (cLUTI or pyelonephritis)

Age category by baseline diagnosis

Duration of IV study treatment

Presence of bacteremia at baseline (yes, no)

Urine sample collected via urinary catheter (yes, no)

Subjects with meropenem- and ceftolozane/tazobactam-resistant baseline 
uropathogens and subjects with meropenem- and ceftolozane/tazobactam-susceptible 
baseline uropathogens

ESBL status of Enterobacteriaceae (ESBL, non-ESBL)

AmpC overexpression status
Additional subgroup analysis summaries for randomized subjects with regard to other factors 
may be considered as needed.
Compliance (Medication Adherence)
Each subject will be scheduled to receive IV study treatment every 8 hours (3 times daily) for 
at least 9 doses. After that, subjects may be switched to open-label, standard-of-care oral step-
down antibiotic therapy at the investigator’s discretion.  Oral step-down therapy is considered 
study treatment.  The total duration of study treatment (IV only or IV + oral) is a minimum of 
7 days and a maximum of 14 days. 
 
 
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In this study, the dosing of IV study treatment will be documented in the study intervention 
CRF page by recording the date, time, and whether or not each dose of IV study treatment was 
completely infused. The amount of oral step-down therapy taken by each subject will be 
recorded in the concomitant medication CRF page.  This information will be used to calculate 
the IV study treatment and overall study treatment compliance rates.  Details of the compliance 
calculations will be provided in the sSAP and/or CSR. 
Extent of Exposure
The extent of exposure during IV study treatment and the total study treatment exposure will 
be summarized as both continuous and categorical variables alongside counts and percentages 
for the “Number of Days on Therapy” by treatment arm in the ASaT population. The summary 
of exposure by treatment arms and age group will also be provided.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
 
 
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Clinical Supplies will be provided by the Sponsor as summarized in Table 16.
Table 16
Product Descriptions
Treatment 
Group
Product Name 
and Dosage 
Form
Dose
Potency
Total 
Dosage 
Forms
Additional 
Information
1
Ceftolozane/
tazobactam-IV
Cohort 
dose
1 g/0.5 g
1.5 g/vial
Commercial 
Zerbaxa product –
clinically labeled
2
Meropenem-IV
Cohort 
dose
1.0 g
1.0 g/vial
Commercial 
meropenem 
product –
clinically labeled
Product Name & 
Potency
Dosage Form
Source/Additional Information
Ceftolozane 1 g/
tazobactam 0.5 g
1 g/0.5 g lyophilized vial
Provided centrally by the Sponsor 
Meropenem 1 g
1 g lyophilized vial
Provided centrally by the Sponsor
All supplies indicated in Table 16 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 16 will be provided by the trial site, 
subsidiary or designee. Every attempt should be made to source these supplies from a single 
lot/batch number. The trial site is responsible for recording the lot number, manufacturer, and 
expiry date for any locally purchased product as per local guidelines unless otherwise 
instructed by the Sponsor.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
The clinical supplies will be open-labeled and each vial/dosage form will contain a component 
identification (CID) number for management of the supplies through an IVRS/IWRS. Subjects 
will receive the IV study treatment following preparation by an unblinded pharmacist (Section 
5.2.6 – Trial Blinding), for a maximum of 14 days. The subject's parent (or guardian) will 
remain blinded to the IV study treatment that the subject receives. Importantly, the unblinded 
pharmacist will be uninvolved in any of the postinfusion evaluations for the subject. All study 
personnel involved with the postinfusion evaluations of safety and efficacy outcomes, 
including the study coordinator(s), investigator, or subinvestigator(s), must have no access to 
the treatment group assignment or the preparation of the study infusion.
 
 
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Clinical Supplies Disclosure
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask IV study treatment identity. In the event that the 
emergency unblinding call center is not available for a given site in this trial, the central 
electronic treatment allocation/randomization system (IVRS/IWRS) should be used in order to 
unblind subjects and to unmask treatment/vaccine identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 7.1.4.4, Subject Blinding/Unblinding, for a description of the method of 
unblinding a subject during the trial, should such action be warranted.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for drug 
accountability and return, or local discard and destruction if appropriate.  Where local discard 
and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial site personnel will have access to a central electronic treatment allocation/randomization 
system (IVRS/IWRS system) to allocate subjects, to assign study treatment to subjects and to 
manage the distribution of clinical supplies. Each person accessing the IVRS system must be 
assigned an individual unique PIN.  They must use only their assigned PIN to access the 
system, and they must not share their assigned PIN with anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will be 
divulged to the institutional review board, ethics review committee (IRB/ERC) or similar or 
 
 
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expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By providing documented informed consent, 
the subject agrees to this process.  If trial documents will be photocopied during the process of 
verifying worksheet/case report form information, the subject will be identified by unique code 
only; full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory submissions, 
and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  Additionally, 
the investigator’s name and business contact information may be included when reporting 
certain serious adverse events to regulatory authorities or to other investigators.  By signing 
this protocol, the investigator expressly consents to these uses and disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating investigators 
upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names and 
qualifications of the IRB/IEC members and to make these records available for regulatory 
agency review upon request by those agencies.
 
 
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Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  The 
investigator/subinvestigator(s) 
further 
agree 
to 
provide 
this 
information 
on 
a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good Clinical 
Practice (e.g., International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all applicable 
federal, state and local laws, rules and regulations relating to the conduct of the clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/IEC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access to 
all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local laws, 
rules and regulations; and, for each subject participating in the trial, provide all data, and, upon 
completion or termination of the clinical trial, submit any other reports to the Sponsor as 
required by this protocol or as otherwise required pursuant to any agreement with the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
 
 
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regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the conduct 
of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, correspondence 
with regulatory authorities and IRBs/ERCs, consent forms, investigator’s curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae.  By signing this protocol, the investigator 
agrees that documentation shall be retained until at least 2 years after the last approval of a 
marketing application in an ICH region or until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  Because the clinical 
development and marketing application process is variable, it is anticipated that the retention 
period can be up to 15 years or longer after protocol database lock. The Sponsor will determine 
the minimum retention period and notify the investigator when documents may be destroyed.  
The Sponsor will determine the minimum retention period and upon request, will provide 
guidance to the investigator when documents no longer need to be retained.  The Sponsor also 
recognizes that documents may need to be retained for a longer period if required by local 
regulatory requirements. All trial documents shall be made available if required by relevant 
regulatory authorities. The investigator must consult with and obtain written approval by the 
Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator will 
immediately disclose in writing to the Sponsor if any person who is involved in conducting the 
trial is debarred or if any proceeding for debarment is pending or, to the best of the 
investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site is 
open in an EU country, Merck, as the Sponsor, will designate, per country, a national principal 
coordinator (Protocol CI), responsible for coordinating the work of the principal investigators 
at the different trial sites in that Member State, according to national regulations.  For a single-
center trial, the Protocol CI is the principal investigator.  In addition, the Sponsor must 
 
 
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designate a principal or coordinating investigator to review the trial report that summarizes the 
trial results and confirm that, to the best of his/her knowledge, the report accurately describes 
the conduct and results of the trial [Clinical Study Report (CSR) CI].  The Sponsor may 
consider one or more factors in the selection of the individual to serve as the Protocol CI and 
or CSR CI (e.g., availability of the Protocol/CSR CI during the anticipated review process, 
thorough understanding of clinical trial methods, appropriate enrollment of subject cohort, 
timely achievement of trial milestones).  The Protocol CI must be a participating trial 
investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialsregister.eu 
or other local registries.  Merck, as Sponsor of this trial, will review this protocol and submit 
the information necessary to fulfill these requirements. Merck entries are not limited to 
FDAAA or the EMA clinical trial directive mandated trials.  Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and functional 
area standard operating procedures (SOPs) to ensure that trials are conducted and data are 
generated, documented, and reported in compliance with the protocol, accepted standards of 
Good Clinical Practice, and all applicable federal, state, and local laws, rules and regulations 
relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her electronic 
signature is the legally binding equivalent of a written signature.  By entering his/her electronic 
signature, the investigator confirms that all recorded data have been verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be provided 
separately.
 
 
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Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided the 
complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also include 
the protocol and statistical analysis plan to facilitate the peer and editorial review of the 
manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will allow 
the journal, if it so desires, to post on its website the key sections of the protocol that are 
relevant to evaluating the trial, specifically those sections describing the trial objectives and 
hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, the 
efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, due 
to statistical concerns.  In rare cases, publication of single trial site data prior to the main paper 
may be of value.  Limitations of single trial site observations in a multicenter trial should 
always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, or 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it 
critically for important intellectual content; and 3) final approval of the version to be published. 
Authors must meet conditions 1, 2 and 3.  Significant contributions to trial execution may also 
be taken into account to determine authorship, provided that contributions have also been made 
to all three of the preceding authorship criteria.  Although publication planning may begin 
before conducting the trial, final decisions on authorship and the order of authors’ names will 
be made based on participation and actual contributions to the trial and writing, as discussed 
above. The first author is responsible for defending the integrity of the data, method(s) of data 
analysis and the scientific content of the manuscript.
 
 
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The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. Any 
information identified by the Sponsor as confidential must be deleted prior to submission; this 
confidentiality does not include efficacy and safety results. Sponsor review can be expedited 
to meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
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Grabe M, Bjerklund-Johansen TE, Botto H, Wullt B, Cek M, Naber KG, et al. 
Guidelines on urological infections. Netherlands: European Association of 
Urology; 2012. 110 p.
[3]
Stamm WE, Norrby SR. Urinary tract infections: disease panorama and 
challenges. J Infect Dis. 2001 Mar 1;183 Suppl 1:S1-4.
[4]
Foxman B. The epidemiology of urinary tract infection. Nat Rev Urol. 2010 
Dec;7(12):653-60.
[5]
Stein R, Dogan HS, Hoebeke P, Kocvara R, Nijman RJ, Radmayr C, et al. 
Urinary tract infections in children: EAU/ESPU guidelines. Eur Urol. 2015 
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[6]
Ma JF, Shortliffe LM. Urinary tract infection in children: etiology and 
epidemiology. Urol Clin North Am. 2004 Aug;31(3):517-26.
[7]
Bader MS, Hawboldt J, Brooks A. Management of complicated urinary tract 
infections in the era of antimicrobial resistance. Postgrad Med. 2010 
Nov;122(6):7-15.
[8]
Center for Drug Evaluation and Research (CDER). Guidance for industry: 
Complicated urinary tract infections: developing drugs for treatment [Internet]. 
Maryland: Department of Health and Human Services Food and Drug 
Administration; 2015 Available from: 
http://www.fda.gov/downloads/Drugs/Guidances/ucm070981.pdf .
[9]
Al Hasan MN, Eckel-Passow JE, Baddour LM. Bacteremia complicating gram-
negative urinary tract infections: a population-based study. J Infect 2010;60:278-
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[10]
Smellie JM, Prescod NP, Shaw PJ, Risdon RA, Bryant TN. Childhood reflux and 
urinary infection: a follow-up of 10-41 years in 226 adults. Pediatr Nephrol. 1998 
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[11]
Benador D, Benador N, Slosman D, Mermillod B, Girardin E. Are younger 
children at highest risk of renal sequelae after pyelonephritis? Lancet. 1997 Jan 
4;349(9044):17-9.
[12]
Larcombe J. Urinary tract infection in children: recurrent infections. BMJ Clin 
Evid. 2015 Jun 12;2015. pii: 0306.
 
 
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[13]
Schulman SL. Voiding dysfunction in children. Urol Clin North Am. 2004 
Aug;31(3):481-90.
[14]
Zorc JJ, Kiddoo DA, Shaw KN. Diagnosis and management of pediatric urinary 
tract infections. Clin Microbiol Rev. 2005 Apr;18(2):417-22.
[15]
Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and 
economic costs. Dis Mon 2003;49:53-70.
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Jacobson SH, Eklof O, Eriksson CG, Lins LE, Tidgren B, Winberg J. 
Development of hypertension and uraemia after pyelonephritis in childhood: 27 
year follow up. BMJ. 1989 Sep 16;299(6701):703-6.
[17]
Spahiu L, Hasbahta V. Most frequent causes of urinary tract infections in 
children. Med Arh. 2010;64(2):88-90.
[18]
Lo DS, Shieh HH, Ragazzi SL, Koch VH, Martinez MB, Gilio AE. Community-
acquired urinary tract infection: age and gender-dependent etiology. J Bras 
Nefrol. 2013 Apr-Jun;35(2):93-8.
[19]
Katsarolis I, Poulakou G, Athanasia S, Kourea-Kremastinou J, Lambri N, 
Karaiskos E, et al. Acute uncomplicated cystitis: from surveillance data to a 
rationale for empirical treatment. Int J Antimicrob Agents. 2010 Jan;35(1):62-7.
[20]
Nicolle LE. Complicated urinary tract infection in adults. Can J Infect Dis Med 
Microbiol. 2005 Nov-Dec; 16(6): 349–360.
[21]
Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-
tazobactam compared with levofloxacin in the treatment of complicated urinary-
tract infections, including pyelonephritis: a randomised, double-blind, phase 3 
trial (ASPECT-cUTI). Lancet. 2015 May 16;385(9981):1949-56.
[22]
Bradley JS, Ang JY, Arrieta AC, Larson KB, Rizk ML, Caro L, et al. 
Pharmacokinetics and safety of single intravenous doses of 
ceftolozane/tazobactam in children with proven or suspected Gram-negative 
infection. Pediatr Infect Dis J. 2018 Nov;37(11):1130-6.
[23]
E.U. Product Circular: Meropenem 500 mg, 1g powder for solution for injection 
or infusion: November 2009.
[24]
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. 
New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009 
Mar;20(3):629-37.
 
 
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[25]
Craig W, Andes D. In Vivo Activities of Ceftolozane, a New Cephalosporin, with 
and without Tazobactam against Pseudomonas aeruginosa and 
Enterobacteriaceae, Including Strains with Extended-Spectrum  -Lactamases, in 
the Thighs of Neutropenic Mice.  Antimicrob Agents Chemother 2013, 57(4): p. 
1577–1582
[26]
Xiao AJ, Caro L, Popejoy MW, Huntington JA, Kullar R. PK/PD Target 
Attainment With Ceftolozane/Tazobactam Using Monte Carlo Simulation in 
Patients With Various Degrees of Renal Function, Including Augmented Renal 
Clearance and End-Stage Renal Disease. Infect Dis Ther. 2016 Dec 24. doi: 
10.1007/s40121-016-0143-9.
[27]
Blumer JL. Meropenem: evaluation of a new generation carbapenem. Int J 
Antimicrob Agents. 1997 Mar;8(2):73-92.
[28]
Romanelli G, Cravarezza P. Intramuscular meropenem in the treatment of 
bacterial infections of the urinary and lower respiratory tracts. Italian 
Intramuscular Meropenem Study Group. J Antimicrob Chemother. 1995 Jul;36 
Suppl A:109-19.
[29]
Cox CE, Holloway WJ, Geckler RW. A multicenter comparative study of 
meropenem and imipenem/cilastatin in the treatment of complicated urinary tract 
infections in hospitalized patients. Clin Infect Dis. 1995 Jul;21(1):86-92.
[30]
Mouton YJ, Beuscart C. Empirical monotherapy with meropenem in serious 
bacterial infections. Meropenem Study Group. J Antimicrob Chemother. 1995 
Jul;36 Suppl A:145-56.
[31]
Schuler D, Meropenem Paediatric Study Group. Safety and efficacy of 
meropenem in hospitalised children: randomised comparison with cefotaxime, 
alone and combined with metronidazole or amikacin. J Antimicrob Chemother 
1995;36(Suppl A):99-108.
[32]
Bradley JS, Faulkner KL, Klaugman KP. Efficacy, safety and tolerability of 
meropenem as empiric antibiotic therapy in hospitalized pediatric patients. 
Pediatr Infect Dis J. 1996 Aug;15(8):749-57.
[33]
Hanna-Wakim RH, Ghanem ST, El Helou MW, Khafaja SA, Shaker RA, Hassan 
SA, et al. Epidemiology and characteristics of urinary tract infections in children 
and adolescents. Front Cell Infect Microbiol. 2015 May 26;5:45.
[34]
Principi N, Marchisio P. Meropenem compared with ceftazidime in the empiric 
treatment of acute severe infections in hospitalized children. Italian Pediatric 
Meropenem Study Group. J Chemother. 1998 Apr;10(2):108-13.
 
 
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[35]
Ahonkhai V, Cyhan GM, Wilson SE, Brown KR. Imipenem-cilastatin in pediatric 
patients: an overview of safety and efficacy in studies conducted in the United 
States. Pediatr Infect Dis J 1989;8:740-4.
[36]
Lee B, Kang SY, Kang HM, Yang NR, Kang HG, Ha IS, et al. Outcome of 
Antimicrobial Therapy of Pediatric Urinary Tract Infections Caused by  
Extended-Spectrum β-Lactamase Producing Enterobacteriaceae. Infect 
Chemother. 2013 Dec;45(4):415-21.
[37]
Karaaslan A, Kadayifci EK, Atici S, Akkoc G, Yakut N, Ocal Demir S, et al. The 
Clinical Efficacy and Safety of Ertapenem for the Treatment of Complicated 
Urinary Tract Infections Caused by ESBL-Producing Bacteria in Children. Int J 
Nephrol. 2015;2015:595840.
[38]
Younis N, Quol K, Al-Momani T, Al-Awaisheh F, Al-Kayed D. Antibiotic 
resistance in children with recurrent or complicated urinary tract infection. JNMA 
J Nepal Med Assoc. 2009 Jan-Mar;48(173):14-9.
[39]
Yildiz B, Kural N, Durmaz G, Yarar C, Ak I, Akcar N. Antibiotic resistance in 
children with complicated urinary tract infection. Saudi Med J. 2007 
Dec;28(12):1850-4.
[40]
Norrby SR, Newell PA, Faulkner KL, Lesky W. Safety profile of meropenem: 
international clinical experience based on the first 3125 patients treated with 
meropenem. J Antimicrob Chemother 1995;36(Suppl A):207-23.
[41]
Solomkin JS, Ristagno RL, Das AF, Cone JB, Wilson SE, Rotstein OD, et al. 
Source control review in clinical trials of anti-infective agents in complicated 
intra-abdominal infections. Clin Infect Dis. 2013 Jun;56(12):1765-73.
[42]
Bradley JS, Jackson MA, Committee on Infectious Diseases, American Academy 
of Pediatrics.The use of systemic and topical fluoroquinolones. Pediatrics. 2011 
Oct;128(4):e1034-45.
[43]
Fasugba O, Gardner A, Mitchell BG, Mnatzaganian G. Ciprofloxacin resistance 
in community- and hospital-acquired Escherichia coli urinary tract infections: a 
systematic review and meta analysis of observational studies. BMC Infect Dis. 
2015 Nov 25;15:545.
[44]
Cohen-Wolkowiez M, Poindexter B, Bidegain M, Weitkamp JH, Schelonka RL, 
Randolph DA, et al. Safety and effectiveness of meropenem in infants with 
suspected or complicated intra-abdominal infections. Clin Infect Dis. 2012 
Dec;55(11):1495-502.
 
 
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[45]
Smith PB, Cohen-Wolkowiez M, Castro LM, Poindexter B, Bidegain M, 
Weitkamp JH, et al. Population pharmacokinetics of meropenem in plasma and 
cerebrospinal fluid of infants with suspected or complicated intra-abdominal 
infections. Pediatr Infect Dis J. 2011 Oct;30(10):844-9.
[46]
Lee LS, Kinzig-Schippers M, Nafziger AN, Ma L, Sörgel F, Jones RN, Drusano 
GL, Bertino JS Jr. Comparison of 30-min and 3-h infusion regimens for 
imipenem/cilastatin and for meropenem evaluated by Monte Carlo simulation. 
Diagn Microbiol Infect Dis. 2010 Nov;68(3):251-8.
[47]
Lancefield RC. A serological differentiation of human and other groups of 
hemolytic streptococci. J Exp Med. 1933 Mar 31;57(4):571-95.
[48]
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law,
only the investigator, Sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Approximate Blood Volumes Drawn/Collected by Trial Visit
The approximate maximum blood volumes to be collected at each trial visit are summarized 
in Table 17.
Table 17
Approximate Blood Volumes Collected by Trial Visit
Approximate Blood Sample Volume (mL)
Trial Period:
Screening
Treatment (7 to 14 days)
Follow-up
Visit Number:
1
3 to 16
17
18
19
20
21
Trial Visit:
Screening
IV Clinical 
Assessments
EOIV 
(all 
subjects)
Oral 
Clinical 
Assessment
(only for IV 
to oral 
switch)
EOT
only for 
IV to oral 
switch)
TOC
(all 
subjects)
LFU a
(all 
subjects)
Safety hematology 
and chemistry, 
serum creatinine
3.5
3.5 b
3.5
3.5
3.5
3.5
3.5 c,d
Coombs test 
(direct)
1.0
0
1.0
0
0
0
0
Serum pregnancy 
test e
3.0
0
0
0
0
3.0 e
0
Blood for culture
7.0 c
7.0 c,f
0
0
0
0
0
Blood for PK 
analyses (Day 3 
only) g
0
0.75 g
0
0
0
0
0
Maximum 
expected total 
blood volume
14.5
11.25
4.5
3.5
3.5
6.5
3.5
EOIV = End of IV Treatment; EOT = End of Treatment; IV = intravenous; LFU = Last Follow-up; PK = 
pharmacokinetics; TOC = Test of Cure
a
At the discretion of the investigator, the LFU Visit may be conducted by telephone, unless the subject has abnormal 
laboratory values or AEs that require follow-up.
b
To be completed on Day 3 and then once weekly while the subject is receiving IV study treatment.
c
If clinically indicated.
d
To be performed only if LFU Visit is conducted in person instead of by telephone.
e
Female subjects of child-bearing potential only. A urine pregnancy test instead of a serum pregnancy test may be 
done at the TOC Visit, if deemed clinically appropriate by the investigator.
f
Blood samples for culture should be collected if signs of sepsis appear at any time during the study.
g
Blood samples for ceftolozane, tazobactam, and tazobactam M1 concentration assays will be collected from all 
subjects over one 8-hour dosing period on Day 3 of the treatment period after administration of at least 6 doses of IV 
study treatment (see Section 7.1.3.7 – Pharmacokinetic Evaluations).
 
 
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List of Abbreviations and Definitions of Terms
Abbreviation or 
Term
Definition
%CV
Coefficient of variation
% fT>MIC
Percentage of dosing interval during which free concentration of drug 
(ceftolozane) exceeds the MIC
% fT>Ct
Percentage of dosing interval during which free concentration of drug 
(tazobactam) exceeds the Ct
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ASaT
All Subjects as Treated
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BLI
β-lactamase inhibitor
BP
Blood pressure
CE
Clinically evaluable
CI
Confidence interval
cIAI
Complicated intra-abdominal infection
CID
Component identification
CL
Clearance
CLSI
Clinical and Laboratory Standards Institute
cLUTI
Complicated lower urinary tract infection
Cmax
Maximum observed concentration
CrCL
Creatinine clearance
CRF
Case report form
CSR
Clinical study report
Ct
Threshold drug concentration
CT
Computed tomography
CVA
Costovertebral angle
CYP450
Cytochrome P450
cIAI
Complicated intra-abdominal infection
cUTI
Complicated urinary tract infection
 
 
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Abbreviation or 
Term
Definition
DAO
Data as observed
DMC
Data Monitoring Committee
ECI
Events of clinical interest
eCRF
Electronic case report form
EDC
Electronic data capture
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Association
EOC
Executive Oversight Committee
EOIV
End of IV Treatment (Visit)
EOT
End of Treatment (Visit)
ERC
Ethics Review Committee
ESBL
Extended-spectrum β-lactamase
EU
European Union
FDA
Food and Drug Administration
FDAAA
FDA Amendments Act
GCP
Good Clinical Practice
Hg
Mercury (for BP, mm Hg)
IAI
Intra-abdominal infection
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IRB
Institutional Review Board
IV
Intravenous
IVRS
Interactive voice response system
IWRS
Integrated web response system
LFU
Last Follow-up (Visit)
M&N
Miettinen and Nurminen (statistical method)
MDR
Multidrug-resistant
ME
Microbiologically evaluable
MIC
Minimum inhibitory concentration
mMITT
Microbiological Modified Intent-to-Treat
MRI
Magnetic resonance imaging
 
 
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Abbreviation or 
Term
Definition
MRSA
Methicillin-resistant Staphylococcus aureus
NP
Nosocomial pneumonia
PCS
Potentially clinically significant
PD
Pharmacodynamic
PIN
Personal identification number
PK
Pharmacokinetic(s)
PTA
Probability of target attainment
Q
Intercompartmental clearance
RBC
Red blood cell
SAE
Serious adverse event
SD
Standard deviation
SOP
Standard operating procedure
sSAP
Supplemental Statistical Analysis Plan
T>MIC
Time above MIC
t½
Elimination half-life
TEAE
Treatment-emergent adverse event
TOC
Test of Cure (Visit)
ULN
Upper limit of normal
US
United States (of America)
UTI
Urinary tract infection
Vc
Central volume of distribution
Vp
Peripheral volume of distribution
WBC
White blood cell
 
 
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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