Clinical trial NCT03217136
Conditions: Complicated Intra-Abdominal Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-04-03; Completion date: 2020-03-16
Enrollment: 94 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Detailed description:

Arms: arm 1: Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days. arm 2: Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for Metronidazole administered IV every 8 hours for 5 to 14 days.
Interventions: intervention 1: Ceftolozane/Tazobactam intervention 2: Metronidazole intervention 3: Meropenem intervention 4: Placebo for Metronidazole
Intervention descriptions: intervention 1: Ceftolozane 20 mg/kg (maximum 1 g) and tazobactam 10 mg/kg (maximum 0.5 g/dose) administered IV every 8 hours for between 5 to 14 days. intervention 2: Metronidazole 10 mg/kg (maximum 1.5 g/day) administered IV every 8 hours for between 5 to 14 days. Participants ≤ 28 days old, start with a loading dose of 15 mg/kg; then if ≤ 2 kg are dosed 7.5 mg/kg/ every 12 hours; or if \> 2 kg are dosed 10 mg/kg every 8 hours. intervention 3: Meropenem 20 mg/kg (maximum 1 g/dose) administered IV every 8 hours for between 5 to 14 days. intervention 4: Placebo for metronidazole administered IV every 8 hours for between 5 to 14 days.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03217136 
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) Plus
Metronidazole Versus Meropenem in Pediatric Subjects with 
Complicated Intra-Abdominal Infection


Product:  MK-7625A 
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Protocol/Amendment No.: 035-03 
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14-Sep-2020
Confidential
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) Plus 
Metronidazole Versus Meropenem in Pediatric Subjects with Complicated Intra-Abdominal 
Infection
IND NUMBER:  104,490
EudraCT NUMBER:  2016-004820-41
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 10
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 16
2.0
TRIAL DESIGN........................................................................................................ 18
Trial Design ........................................................................................................... 18
Trial Diagram........................................................................................................ 21
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 21
Primary Objective(s) & Hypothesis(es).............................................................. 21
Secondary Objective(s) & Hypothesis(es)........................................................... 21
Exploratory Objectives......................................................................................... 22
4.0
BACKGROUND & RATIONALE.......................................................................... 22
Background ........................................................................................................... 22
Pharmaceutical and Therapeutic Background .................................................... 22
Ceftolozane/Tazobactam.............................................................................. 22
Complicated Intra-abdominal Infection....................................................... 23
Completed Preclinical and Clinical Trials of Ceftolozane/Tazobactam............. 25
Ongoing Clinical Trials of Ceftolozane/Tazobactam ......................................... 26
Information on Other Trial-related Therapy....................................................... 26
Comparator Therapy.................................................................................... 26
Metronidazole for Adjunctive Anaerobic Coverage.................................... 27
Rationale................................................................................................................ 27
Rationale for the Trial and Selected Subject Population .................................... 27
Rationale for Sample Size............................................................................ 28
Rationale for Dose Selection/Regimen............................................................... 28
Rationale for Ceftolozane/Tazobactam Dosage........................................... 28
Rationale for Metronidazole Dosage ........................................................... 32
Rationale for the Use of Comparator........................................................... 32
Rationale for Comparator Dosage ............................................................... 32
 
 
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Rationale for Duration of Therapy and Optional Oral Step-Down 
Antibiotic Therapy....................................................................................... 33
Rationale for Endpoints ...................................................................................... 34
Rationale for Safety Endpoints.................................................................... 34
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 .................................................................................. 41
Trial Treatment(s) ................................................................................................ 44
Intravenous Trial Treatments.............................................................................. 44
Optional Oral Step-down Therapy...................................................................... 47
Trial Treatments: Administrative Considerations............................................... 48
Dose Selection .................................................................................................... 48
Dose Selection (Preparation) ....................................................................... 48
Timing of Dose Administration.......................................................................... 48
Trial Blinding...................................................................................................... 49
Randomization ...................................................................................................... 49
Stratification.......................................................................................................... 49
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 49
Rescue Medications & Supportive Care............................................................. 51
Diet/Activity/Other Considerations..................................................................... 51
Subject Withdrawal/Discontinuation Criteria................................................... 51
Discontinuation of Treatment ............................................................................. 51
Withdrawal from the Trial .................................................................................. 52
Subject Replacement Strategy............................................................................. 52
Beginning and End of the Trial ........................................................................... 52
 
 
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Clinical Criteria for Early Trial Termination ................................................... 53
6.0
TRIAL FLOW CHART ........................................................................................... 54
7.0
TRIAL PROCEDURES ........................................................................................... 57
Trial Procedures ................................................................................................... 57
Administrative Procedures.................................................................................. 57
Informed Consent/Assent............................................................................. 57
7.1.1.1.1
General Informed Consent/Assent........................................................ 57
Inclusion/Exclusion Criteria ........................................................................ 58
Subject Identification Card .......................................................................... 58
Medical History ........................................................................................... 58
Prior and Concomitant Medications Review............................................... 58
7.1.1.5.1
Prior Medications.................................................................................. 58
7.1.1.5.2
Concomitant Medications..................................................................... 59
Assignment of Screening Number............................................................... 59
Assignment of Treatment/Randomization Number..................................... 59
Trial Compliance (Medication).................................................................... 59
Clinical Procedures/Assessments........................................................................ 59
Body Weight, Height, and Vital Signs......................................................... 59
Physical Examination................................................................................... 60
Surgical Wound Examination...................................................................... 60
Abdominal Sign and Symptom Assessment................................................ 60
Summary of Operative Procedures .............................................................. 61
Radiological Examination............................................................................ 61
Adverse Event Monitoring........................................................................... 61
Assessment of Clinical Outcome................................................................. 61
Assessment of Microbiological Outcome.................................................... 61
Assessment of Emergent Infection .............................................................. 61
Laboratory Procedures/Assessments .................................................................. 61
Laboratory Safety Evaluations (Hematology and Chemistry)..................... 62
Pregnancy Testing........................................................................................ 63
Assessment of Creatinine Clearance............................................................ 63
Intra-abdominal Samples for Culture........................................................... 63
 
 
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Blood Samples for Culture........................................................................... 64
Pharmacokinetic Evaluations....................................................................... 64
Other Procedures................................................................................................. 64
Withdrawal/Discontinuation........................................................................ 64
Lost to Follow-up......................................................................................... 65
Unblinded Pharmacist.................................................................................. 65
Subject Blinding/Unblinding ....................................................................... 65
Calibration of Critical Equipment................................................................ 66
Visit Requirements.............................................................................................. 66
Screening...................................................................................................... 66
Randomization Visit .................................................................................... 67
Clinical Assessment Visits on Intravenous Study Treatment...................... 67
End of IV Treatment Visit ........................................................................... 67
Clinical Assessment Visit on Oral Step-down Therapy .............................. 67
End of Treatment Visit................................................................................. 68
Test of Cure Visit......................................................................................... 68
Last Follow-up Visit .................................................................................... 68
Subjects Who Prematurely Discontinue From Study Treatment or the 
Trial.............................................................................................................. 68
Assessing and Recording Adverse Events .......................................................... 68
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 69
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 69
Immediate Reporting of Adverse Events to the Sponsor.................................... 70
Serious Adverse Events ............................................................................... 70
Events of Clinical Interest............................................................................ 71
Evaluating Adverse Events................................................................................. 72
Sponsor Responsibility for Reporting Adverse Events ...................................... 75
TRIAL GOVERNANCE AND OVERSIGHT................................................... 75
Executive Oversight Committee......................................................................... 75
Data Monitoring Committee............................................................................... 75
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 75
Statistical Analysis Plan Summary ..................................................................... 76
 
 
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Responsibility for Analyses/In-house Blinding .................................................. 77
Hypotheses/Estimation ......................................................................................... 78
Analysis Endpoints ............................................................................................... 78
Safety Endpoints ................................................................................................. 78
Adverse Events ............................................................................................ 78
Laboratory Data ........................................................................................... 78
Vital Signs.................................................................................................... 79
Efficacy Endpoints.............................................................................................. 79
Secondary Efficacy Endpoints..................................................................... 79
Exploratory Efficacy Endpoints................................................................... 79
Pharmacokinetic Endpoints ................................................................................ 80
Analysis Populations............................................................................................. 80
Safety Analysis Populations ............................................................................... 80
Efficacy Analysis Populations ............................................................................ 80
Statistical Methods................................................................................................ 81
Statistical Methods for Safety Analyses ............................................................. 81
Statistical Methods for Efficacy Analyses.......................................................... 83
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 85
Analyses of Baseline Characteristics and Demographics............................ 85
Population Pharmacokinetic Analyses......................................................... 86
Interim Analyses ................................................................................................... 86
Multiplicity ............................................................................................................ 86
Sample Size and Power Calculations .................................................................. 86
Subgroup Analyses ............................................................................................... 87
Compliance (Medication Adherence).................................................................. 88
Extent of Exposure................................................................................................ 88
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 88
Investigational Product ........................................................................................ 88
Packaging and Labeling Information ................................................................. 89
Clinical Supplies Disclosure................................................................................. 90
Storage and Handling Requirements.................................................................. 90
 
 
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Discard/Destruction/Returns and Reconciliation .............................................. 90
Standard Policies................................................................................................... 90
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 91
Confidentiality....................................................................................................... 91
Confidentiality of Data ....................................................................................... 91
Confidentiality of Subject Records..................................................................... 91
Confidentiality of Investigator Information........................................................ 91
Confidentiality of IRB/IEC Information............................................................. 92
Compliance with Financial Disclosure Requirements....................................... 92
Compliance with Law, Audit and Debarment ................................................... 92
Compliance with Trial Registration and Results Posting Requirements ........ 94
Quality Management System............................................................................... 94
Data Management................................................................................................. 94
Publications ........................................................................................................... 95
11.0
LIST OF REFERENCES......................................................................................... 96
12.0
APPENDICES........................................................................................................... 99
Merck Code of Conduct for Clinical Trials........................................................ 99
Approximate Blood Volumes Drawn/Collected by Trial Visit....................... 101
List of Abbreviations and Definitions of Terms............................................... 102
13.0
SIGNATURES......................................................................................................... 105
Sponsor's Representative ................................................................................... 105
Investigator.......................................................................................................... 105
 
 
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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
Emergent Infection Categories ............................................................................... 38
Table 6
Intravenous Trial Treatments.................................................................................. 44
Table 7
Recommended Oral Step-down Therapy Options.................................................. 47
Table 8
Laboratory Safety Evaluations................................................................................ 62
Table 9
Evaluating Adverse Events..................................................................................... 73
Table 10 Efficacy Analysis Populations................................................................................ 81
Table 11 Analysis Strategy for Safety Parameters................................................................ 82
Table 12 Analysis Strategy for Efficacy Variables ............................................................... 84
Table 13 Estimated Two-sided 95% Confidence Intervals Based on Different Assumed 
Observed Rates of Efficacy Endpoints................................................................... 84
Table 14 Estimated Treatment Differences and Two-sided 95% Confidence Intervals ....... 87
Table 15 Product Descriptions .............................................................................................. 89
Table 16 Approximate Blood Volumes Collected by Trial Visit........................................ 101
 
 
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LIST OF FIGURES
Figure 1
Trial Diagram...................................................................................................... 21
 
 
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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 cIAI (MK-7625A-035) and also in the companion 
trial in pediatric subjects with cUTI (MK7625A-034), 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 cIAI (MK-7625A-035) and the companion trial in 
pediatric subjects with cUTI (MK-7625A-034).
Amendment 1/
Ukraine specific amendment
30-APR-2018
Country-specific amendment to exclude enrollment of subjects <2 years old 
(Groups 4 and 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
Rationale for Sample Size
Intravenous Trial Treatments
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
10.1.2
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
Confidentiality of Subject 
Records
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
2.1
5.1.2
Trial Design
Subject Inclusion Criteria
Reworded language regarding 
the enrollment target for the 
percentage of subjects with a 
diagnosis 
of 
complicated 
appendicitis.
To provide additional flexibility in 
the number of subjects enrolled 
with a diagnosis of complicated 
appendicitis.
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 5: “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.
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.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
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.
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.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
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. 
Global
Global
Minor editorial and document 
formatting revisions.
Minor syntax and grammar edits 
made for clarity and correctness.
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
MK-7625A Plus Metronidazole versus Meropenem in Pediatric cIAI
Sponsor Product Identifiers
MK-7625A
Ceftolozane/tazobactam
Trial Phase
2
Clinical Indication
Treatment of complicated intra-abdominal infection (cIAI)
Trial Type
Interventional
Type of control
Active control 
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 + metronidazole) or comparator (meropenem + 
placebo) 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 and 
metronidazole 10 mg/kg IV every 8 hours (maximum dose 1.5 g/day) 
OR
Meropenem 20 mg/kg (maximum 1 g/dose) IV every 8 hours and 
placebo for metronidazole 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 and 
metronidazole 10 mg/kg IV every 8 hours (maximum dose 1.5 g/day) 
OR
Meropenem 20 mg/kg (maximum 1 g/dose) IV every 8 hours and 
placebo for metronidazole IV every 8 hours
Group 3 (Ages 2 to <6 years, n≥57 combined with same age group in 
MK-7625A-034:
Ceftolozane 
20 mg/kg 
and 
tazobactam 
10 mg/kg 
(maximum 
ceftolozane 1 g and tazobactam 0.5 g/dose) IV every 8 hours and 
metronidazole 10 mg/kg IV every 8 hours (maximum dose 1.5 g/day) 
OR
Meropenem 20 mg/kg (maximum 1 g/dose) IV every 8 hours and 
placebo for metronidazole IV every 8 hours
Group 4 (Ages 3 months to <2 years, n≥24 combined with same age 
group in MK-7625A-034:
Ceftolozane 
20 mg/kg 
and 
tazobactam 
10 mg/kg 
(maximum 
ceftolozane 1 g and tazobactam 0.5 g/dose) IV every 8 hours and 
metronidazole 10 mg/kg IV every 8 hours (maximum dose 1.5 g/day) 
OR
Meropenem 20 mg/kg (maximum 1 g/dose) IV every 8 hours and 
placebo for metronidazole 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-034:
 
 
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Ceftolozane 
20 mg/kg 
and 
tazobactam 
10 mg/kg 
(maximum 
ceftolozane 1 g and tazobactam 0.5 g/dose) IV every 8 hours and 
metronidazole IV every 8-12 hours (see below for metronidazole dosing 
for Group 5)
OR
Meropenem 20 mg/kg* (maximum 1 g/dose) IV every 8 hours and 
placebo for metronidazole 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.
Metronidazole Dosing for Group 5
Subjects >28 days of age:
Metronidazole 10 mg/kg every 8 hours (maximum dose 1.5 g/day)
For subjects ≤28 days of age the suggested dosing regimen is listed 
below; however, other site-specific standard of care metronidazole 
dosing may be used at the investigator’s discretion.
Subjects ≤28 days of age and ≤2 kg:
Metronidazole 15 mg/kg loading dose, then 7.5 mg/kg/dose every 12 
hours
Subjects ≤28 days of age and >2 kg:
Metronidazole 15 mg/kg loading dose, 10 mg/kg dose every 8 hours
NOTE: 

Subjects 7 to 28 days of age who receive metronidazole with a 
frequency other than every 8 hours must receive placebo at the 
same frequency to maintain blinding.

In Ukraine, enrollment will be limited to subjects 2 years to < 18 
years of age (Groups 1-3). Enrollment of subjects < 2 years old 
(Groups 4-5) is not applicable at Ukrainian study sites.
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 5 days 
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 7 to 
14 days after the last dose of study treatment and a Last Follow-up 
(LFU) Visit 21 to 28 days after the last dose of study treatment.
Randomization Ratio
3:1 for ceftolozane/tazobactam + metronidazole: meropenem + 
placebo
 
 
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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) plus 
metronidazole versus meropenem plus placebo in pediatric subjects from birth (defined as 
>32 weeks gestational age and ≥7 days postnatal) to <18 years of age with complicated intra-
abdominal infection (cIAI). 
MK-7625A-034 
is 
a 
companion
Phase 
2
randomized, 
double-blind 
trial 
of 
ceftolozane/tazobactam versus meropenem in pediatric subjects with cUTI; 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.
NOTE: Approximately 90% of the randomized population will consist of subjects with a 
diagnosis of complicated appendicitis. 
In MK-7625A-035, subjects will be randomized in a 3:1 ratio to receive IV 
ceftolozane/tazobactam plus metronidazole or meropenem plus placebo. 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 5 days and a 
maximum of 14 days.
Subjects will be randomized to the experimental (ceftolozane/tazobactam + metronidazole) 
or comparator (meropenem + placebo) 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 and metronidazole 10 mg/kg IV 
every 8 hours (maximum dose 1.5 g/day) 
OR
Meropenem 20 mg/kg (maximum of 1 g/dose) IV every 8 hours and placebo for 
metronidazole IV every 8 hours
 
 
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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 and metronidazole 10 mg/kg IV every 8 hours (maximum dose 
1.5 g/day) 
OR
Meropenem 20 mg/kg (maximum of 1 g/dose) IV every 8 hours and placebo for 
metronidazole IV every 8 hours
Group 3 (Ages 2 to <6 years, n≥57 combined with same age group in MK-7625A-034:
Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum ceftolozane 1 g and tazobactam 
0.5 g/dose) IV every 8 hours and metronidazole 10 mg/kg IV every 8 hours (maximum dose 
1.5 g/day) 
OR
Meropenem 20 mg/kg (maximum of 1 g/dose) IV every 8 hours and placebo for 
metronidazole IV every 8 hours
Group 4 (Ages 3 months to <2 years, n≥24 combined with same age group in MK-7625A-
034:
Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum ceftolozane 1 g and tazobactam 
0.5 g/dose) IV every 8 hours and metronidazole 10 mg/kg IV every 8 hours (maximum dose 
1.5 g/day) 
OR
Meropenem 20 mg/kg (maximum of 1 g/dose) IV every 8 hours and placebo for 
metronidazole 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-034:
Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum ceftolozane 1 g and tazobactam 
0.5 g/dose) IV every 8 hours and metronidazole IV every 8 to 12 hours (see Table 6 for 
metronidazole dosing in Group 5)
OR
Meropenem 20 mg/kg* (maximum of 1 g/dose) IV every 8 hours and placebo for 
metronidazole 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:

Subjects 7 to 28 days of age who receive metronidazole dosing with a frequency other 
than every 8 hours must receive placebo dosing at the same frequency to maintain 
blinding.
 
 
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
In Ukraine, enrollment will be limited to subjects 2 years to < 18 years of age 
(Groups 1-3). Enrollment of subjects < 2 years old (Groups 4-5) 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 cIAI:
Primary Objective(s) & Hypothesis(es)
To evaluate the safety and tolerability of ceftolozane/tazobactam plus metronidazole 
compared with that of meropenem
Secondary Objective(s) & Hypothesis(es)
1. To evaluate the efficacy of ceftolozane/tazobactam plus metronidazole compared 
with that of meropenem with respect to clinical response at the EOT and TOC Visits
 
 
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2. To evaluate the efficacy of ceftolozane/tazobactam plus metronidazole 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 plus metronidazole compared 
with that of meropenem with respect to clinical response at the EOIV Visit
3. To evaluate the efficacy of ceftolozane/tazobactam plus metronidazole compared 
with that of meropenem with respect to per-subject microbiological response at the 
EOIV Visit
4. To evaluate the efficacy of ceftolozane/tazobactam plus metronidazole compared 
with that of meropenem with respect to per-pathogen 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 
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 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 
 
 
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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 shown 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 shown in Phase 3 trials in adult 
subjects with complicated urinary tract infections (cUTI) and cIAI. In these Phase 3 trials, the 
overall incidence of 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.
Complicated Intra-abdominal Infection
Uncomplicated IAI is characterized by involvement of a single infected abdominal organ 
without anatomical disruption; in contrast, cIAI is characterized by extension of infection 
into the peritoneal space, manifesting as abdominal abscess or diffuse peritonitis [1].
Primary peritonitis, defined as microbial infection of the peritoneum and peritoneal fluid 
without accompanying gastrointestinal (GI) or other visceral perforation, abscess or localized 
IAI, rarely develops in healthy adults but mainly occurs in infancy and early childhood and in 
adult cirrhotic patients [2]. Secondary peritonitis, the most common form of cIAI, typically 
 
 
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results from loss of integrity of the GI tract or infected viscera. Common causes of secondary 
bacterial peritonitis include penetrating or blunt abdominal trauma, appendicitis, 
diverticulitis, gastroduodenal ulcer perforation, biliary tract infections, and postoperative 
complications after abdominal procedures. Necrotizing enterocolitis (NEC), an inflammatory 
bowel necrosis that generally presents within the first 2 weeks of life and affects the terminal 
ileum, is the most common cause of secondary peritonitis in neonates [3]. In older pediatric 
patients, secondary peritonitis is predominantly associated with complicated appendicitis, 
although it also occurs as a result of intussusception, incarcerated hernia, volvulus, or rupture 
of a Meckel’s diverticulum. In a study of community-acquired cIAI in pediatric patients aged 
from 1 month to 15 years, the vast majority of infections were complicated appendicitis 
(113/123, 92%) [4]. Complicated appendicitis arising from ruptured or gangrenous acute 
appendicitis is associated with significant increases in morbidity and length of 
hospitalization; perforation rates are as high as 82% for pediatric patients under 5 years and 
100% for pediatric patients under 1 year [5].
The microbiology of cIAI is predominantly related to the site of loss of integrity within the 
GI tract and the level of disruption; as the lower GI tract contains hundreds of bacterial 
species at high concentrations, cIAI arising from the lower GI tract is likely to be 
polymicrobial in nature [6]. Infections derived from the colon are linked with facultative and 
obligate anaerobic organisms, gram-negative organisms (Enterobacteriaceae), other gram-
negative bacilli and enterococci [6]. In a study of 100 pediatric patients with ruptured 
appendices, 144 aerobic isolates and 310 anaerobic isolates were detected, with the 
predominant aerobic bacteria being E. coli, alpha-hemolytic streptococci, gamma-hemolytic 
streptococci, group D enterococcus, and P. aeruginosa. Gram-negative bacilli (Bacteroides 
fragilis group and pigmented Prevotella and Porphyromonas), gram-positive anaerobic 
cocci, Fusobacterium spp, and Clostridium spp were the most common anaerobic isolates [7]. 
NEC is associated with fewer anaerobic isolates; aerobic species including Klebsiella, 
Enterobacter and Streptococcus spp are instead frequently reported.
Nosocomially-acquired pathogens associated with a high degree of antibiotic resistance 
include strains of P. aeruginosa, S. marcescens, Acinetobacter, and Providencia spp. 
Furthermore, drug-resistant pathogens such as ESBL-producing Enterobacteriaceae, 
methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci 
may present in cIAI [8].
Intra-abdominal infection typically presents with acute onset abdominal pain associated with 
symptoms of gastrointestinal dysfunction such as anorexia, nausea or vomiting. In addition 
patients with cIAI will often display systemic signs of inflammation. A perforated viscera is 
likely to induce a systemic response, and such patients will often be febrile and tachycardic
[9].
The treatment of cIAI involves a multifaceted approach including a source control procedure 
to drain infected foci and control ongoing peritoneal contamination as well as adjunctive 
antimicrobial treatment.
The importance of antimicrobial therapy selection has been highlighted in an analysis of 
clinical data generated in the Netherlands, which showed that hospitalized patients with 
 
 
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nosocomial cIAI who had not been administered appropriate therapy (16%) were at over 
3-fold higher risk of clinical failure in relation to those that had. As a result, antimicrobial 
selection has significant implications in relation to both patient care and associated health
care costs [2].
As cIAI is associated with mixed aerobic and anaerobic bacteria that act in synergy to 
increase pathogenicity, appropriate antimicrobial therapy should include either broad-
spectrum agents or drug combinations to effectively combat infection. Thus, broad-spectrum 
empiric therapy of suspected or confirmed pediatric cIAI is indicated and treatment with 
carbapenems (imipenem or meropenem), piperacillin-tazobactam, ticarcillin-clavulanate, or 
an extended-spectrum cephalosporin (cefotoxime, ceftriaxone, ceftazidime, or cefepime) 
with metronidazole is recommended [10].
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 cIAI indication 
was derived from 2 large, identical, global, multicenter, randomized, double-blind, 
active-controlled Phase 3 trials (CXA-cIAI-10-08 [MK-7625A-003] and CXA-cIAI-10-09 
[MK-7625A-004]). In both trials, adult subjects were randomized 1:1 to receive either IV 
ceftolozane/tazobactam 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) every 8 hours plus 
metronidazole 500 mg every 8 hours or IV meropenem 1 g every 8 hours administered for 
4 to 14 days. The results indicated that ceftolozane/tazobactam plus metronidazole was 
noninferior to meropenem in the treatment of cIAI in adults.
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 to 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 frequently
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) [11]. 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 
 
 
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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 versus meropenem in pediatric subjects with cUTI, including 
pyelonephritis, 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
Comparator Therapy
Subjects in the comparator arm of the present trial will receive IV meropenem (Table 6).
Meropenem is a carbapenem antibiotic indicated as single-agent therapy for the treatment of 
complicated appendicitis and peritonitis caused by viridans group streptococci, E. coli, 
Klebsiella 
pneumoniae, 
P. 
aeruginosa, 
B. 
fragilis 
B. thetaiotaomicron, 
and 
Peptostreptococcus species. See Section 4.2.2.3 – Rational for the Use of Comparator and 
Section 4.2.2.4 – Rationale for Comparator Dosage for additional details on the efficacy and 
safety of meropenem in the treatment of cIAI. 
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 
 
 
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concentrations exceeded the MIC of the infecting organisms for approximately 40% of the 
dosing interval.
Metronidazole for Adjunctive Anaerobic Coverage
Subjects in the ceftolozane/tazobactam arm of this trial will receive adjunctive therapy with 
IV metronidazole (Table 6).
Metronidazole injection, USP, is a parenteral formulation of the synthetic nitroimidazole 
antibacterial agent 2-methyl-5-nitro-1H-imidazole-1-ethanol. 
The addition of metronidazole in combination with ceftolozane/tazobactam ensures coverage 
of intra-abdominal infections caused by anaerobic bacteria including Bacteroides species 
including the B. fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, 
B vulgatus), Clostridium species, Eubacterium species, Peptococcus species,
and 
Peptostreptococcus species.
Metronidazole is recommended as part of combination therapy for empiric treatment of cIAI 
in children in the Infectious Diseases Society of America (IDSA) guidelines on treatment of 
cIAI [1].
Rationale
Rationale for the Trial and Selected Subject Population
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 cIAI or cUTI. 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 used 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 
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-035) will enroll pediatric subjects from birth to <18 years of 
age (from 2 years to < 18 years of age in Ukraine) who present with cIAI 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 [12], which will be used to 
calculate renal function in this population, is not recommended for use until after the first 
 
 
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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 cIAI.  The efficacy of ceftolozane/tazobactam in pediatric subjects 
with cIAI 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-034 (the companion trial in pediatric subjects with cUTI) (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. In addition, a minimum 
enrollment target of at least 4 subjects in Groups 3-5 are in place to ensure data are obtained 
for these age groups from subjects with cIAI. 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. 
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.
 
 
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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 [13]. 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 [14]. Time above a Ct
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 Metronidazole Dosage
Data on the PK and ideal dosing of metronidazole in pediatric patients are limited, especially 
for pediatric patients less than 1 month of age. As a result, dosing recommendations are 
highly variable without an accepted standard [15]. Suggested dosing recommendations for 
subjects <1 month old outlined in the protocol are based on one of the more frequently used 
dosing schedules [16]. However, to allow for potential variations in metronidazole dosing 
between different sites participating in this trial, the protocol allows for the use of site-
specific standard of care dosing in subjects <1 month of age. Sites that use dosing schedules 
other than every 8 hours must adjust the blinding of placebo in subjects randomized to the 
meropenem arm.
In older pediatric patients, metronidazole dosing is more standardized. The dose of 
metronidazole for pediatric patients >1 month old chosen for this trial (30 mg/kg divided 
every 8 hours) is based on dosing recommendations from the IDSA guidelines on treatment 
of cIAI [1].
Rationale for the Use of Comparator
As described in Section 4.1.4.1 – Comparator Therapy, meropenem is indicated for treatment 
of IAI in adult and pediatric patients (3 months of age and older) caused by single or multiple 
bacteria sensitive to meropenem.
Meropenem is also one of several regimens recommended for empiric treatment of cIAI in 
pediatric patients by the Surgical Infection Society and IDSA current treatment guidelines [1]
and there is significant clinical experience from both clinical trials and post-marketing data 
for the use of meropenem in the treatment of pediatric cIAI. It is the optimal choice of 
comparator for ceftolozane/tazobactam as the every 8-hour dosing interval facilitates 
blinding.
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 the companion Phase 2 trial of 
ceftolozane/tazobactam in pediatric subjects with cUTI (MK-7625A-034), which also utilizes 
meropenem as the comparator (see Section 4.2.1.1 – Rationale for Sample Size). Available 
Phase 3 comparative safety data for ceftolozane/tazobactam versus meropenem from trials in 
adults with cIAI [1] will allow comparison of the safety profiles of ceftolozane/tazobactam 
and meropenem in pediatric and adult subjects.
Rationale for Comparator Dosage
The meropenem dose for Groups 1 through 4 (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 
cIAI [17].
 
 
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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 showed that meropenem was safe and well tolerated at the 20 mg/kg dose
[15]. 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 [18]. 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 prescribing information) [17] 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 [19].
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 cIAI.
Rationale for Duration of Therapy and Optional Oral Step-Down Antibiotic 
Therapy 
Current guidelines for the treatment of cIAI recommend 4 to 7 days of antibiotic therapy 
after adequate source control is achieved [1]. However, some types of pediatric cIAI, such as 
NEC, may require a longer duration of therapy of up to 14 days. Because subjects may be
enrolled and started on study treatment before adequate source control is achieved and 
because some types of pediatric cIAI may require longer treatment courses, subjects in the 
present trial will receive 5 to 14 days of IV study treatment.
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. 
 
 
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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). 
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 success rate at the EOT and TOC Visits, defined as the 
proportion of subjects in the analysis population who have microbiological 
eradication or presumed eradication of all baseline pathogens.
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. 
 
 
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
Per-subject microbiological success rate at the EOIV Visit, defined as the proportion 
of subjects in the analysis population who have a microbiological outcome of 
eradication or presumed eradication of all baseline pathogens.

Per-pathogen microbiological success rate at the EOIV, EOT, and TOC Visits, 
defined as the proportion of baseline pathogens that have an outcome of 
microbiological eradication or presumed 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.
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.
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 before 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 cIAI or return to preinfection signs and symptoms 
such that no further antibiotic therapy (IV or oral) or surgical or 
drainage procedure is required for treatment of the cIAI.
Partial improvement 
(only at the EOIV Visit for subjects 
who switch to oral step-down therapy)
Partial resolution of signs and symptoms of the cIAI such that no 
further IV antibiotic therapy is required for the treatment of the 
cIAI; however, additional oral step-down therapy is required.
Failure 
Any of the following is considered a clinical outcome of failure:

Requirement of antibiotic therapy beyond the protocol-defined 
treatment duration of 14 days.

Persisting or recurrent infection within the abdomen requiring 
additional intervention, including nonstudy antibiotics or repeat 
surgical intervention.
NOTE: Repeat percutaneous aspiration of an abscess within 72 
hours of the original aspiration, without worsening clinical 
signs and symptoms, is not considered a failure. However, the 
need to repeat any procedure after 72 hours of study treatment 
to cure the infection should be considered a failure. 
Exploratory or diagnostic procedures with no evidence of an 
ongoing infection are not considered a failure.

Post-surgical wound infection with signs of local infection, 
such as purulent exudate, erythema, or warmth that requires 
additional antimicrobial therapy and/or nonroutine wound care.

Death related to IAI
Indeterminate
Trial data are not available for evaluation of efficacy for any 
reason, including death during the trial period unrelated to the cIAI 
or extenuating circumstances which preclude classification as cure, 
partial improvement, or failure (eg, subject is lost to follow-up).
cIAI = complicated intra-abdominal infection; EOIV = End of IV Treatment; IV = intravenous
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, presumed eradication, persistence, presumed persistence, 
persistence acquiring resistance, and indeterminate as defined in Table 4. Eradication or 
presumed eradication will be considered favorable microbiological responses; in order for the 
subject to have a favorable overall microbiological response (ie, eradication or presumed 
eradication), each baseline pathogen must have a favorable microbiological outcome.
 
 
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Per-pathogen Microbiological Outcome
The per-pathogen microbiological outcome will be determined for each baseline infecting 
pathogen isolated by the Sponsor (see Table 4). Eradication or presumed eradication will be 
considered favorable microbiological responses. 
Table 4
Microbiological Outcome Categories
Outcomea
Definitiona
Eradicationb
Absence of the baseline pathogen(s) in a postbaseline specimen 
appropriately obtained from the original site of infection.
Presumed eradicationb
Absence of material to culture in a subject who is assessed as having 
partial improvement, or clinical cure.
Persistence
Presence of the baseline pathogen(s) in an appropriately obtained 
postbaseline specimen from the site of infection or surgical wound.
NOTE: Cultures from indwelling drains are not considered appropriate. 
Presumed persistence
Absence of material to culture in a subject who is assessed as a clinical 
failure.
Persistence acquiring resistance
Presence of baseline pathogen(s) in an appropriately obtained 
postbaseline specimen where the baseline pathogen(s) was susceptible to 
study treatment pretreatment and is resistant to study treatment post-
treatment.
Indeterminate

Baseline culture either not obtained or has no growth.

Postbaseline culture was not obtained and clinical assessment was 
not possible.

Any other circumstance that makes it impossible to define the 
microbiological response (eg, subject lost to follow-up).
a
The per-pathogen microbiological outcome will be determined for each baseline infecting pathogen 
isolated by the Sponsor.
b
Eradication or presumed eradication will be considered favorable microbiological responses.
Emergent Infection
Pathogens isolated after baseline will be assessed for the outcome of superinfection or new 
infection, as defined in Table 5.
 
 
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Table 5
Emergent Infection Categories
Outcome
Definition
Superinfection
Isolation of a pathogen, other than the original baseline pathogen(s), 
from an appropriately obtained postbaseline specimen in a subject while 
on study treatment.
New infection
Isolation of a pathogen, other than the original baseline pathogen(s), 
from an appropriately obtained postbaseline specimen in a subject after 
administration of the last dose of study treatment and through the 
TOC visit.
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 7.1.3.6 – 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.
This trial will include pediatric subjects who require IV antibiotics for treatment of cIAI. If 
randomized to receive ceftolozane/tazobactam + metronidazole, subjects will receive an 
antibiotic regimen that is active against organisms frequently isolated from pediatric patients 
with cIAI and that has proven to be effective in large-scale clinical trials for the treatment of 
cIAI 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 
cIAI in pediatric patients 3 months of age and older and adults (Section 4.1.4.1 – Comparator 
Therapy).
 
 
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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, physical examinations, 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 cIAI 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 will be limited to 2 
years to < 18 years (Groups 1-3). Subjects < 2 years old (Groups 4-5) are not 
permitted to enroll into the study at Ukrainian sites.
3.
Be able to comply with the protocol for the duration of the trial.
4.
Require IV antibacterial therapy for the treatment of presumed or documented cIAI 
as demonstrated by either:
Operative diagnosis (laparotomy, laparoscopy or percutaneous drainage) of cIAI, 
defined as evidence of infection within the abdominal cavity extending beyond the 
hollow viscus of origin into the peritoneal space as demonstrated by either abscess 
formation or peritonitis.
OR
Preoperative diagnosis of cIAI, defined as meeting both of the criteria below:
a) Clinical evidence of cIAI as indicated by one or more systemic signs or 
symptoms that accompany cIAI, such as fever, leukocytosis, hypotension, 
 
 
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abdominal pain, nausea/vomiting, anorexia, abdominal mass on clinical 
examination, or altered mental status. 
b) Radiographic evidence consistent with cIAI.
NOTE: Approximately 90% of the randomized population will consist of subjects 
with a diagnosis of complicated appendicitis.
5.
Have an operative procedure for the current diagnosis and management of cIAI 
planned or completed within 24 hours of the first dose of an antibacterial drug.
NOTE: Subjects with a diagnosis of NEC are exempt from this inclusion criteria and 
are not required to have surgery planned or completed in order to be eligible for 
enrollment. 
6.
Have baseline intra-abdominal specimen collection in compliance with Section 
7.1.3.4 – Intra-abdominal Samples for Culture. Subjects enrolled preprocedure
should have a sample obtained during the interventional procedure performed to 
comply with Section 7.1.3.4.
NOTE: Subjects with NEC that do not require surgical intervention are exempt from 
this inclusion criteria and are not required to have an intra-abdominal culture. 
7.
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 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 childbearing.
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 

Vasectomy of a female subject’s male partner 

Contraceptive rod implanted into the skin
 
 
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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 used 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.
8.
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 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.
 
 
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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), β-lactamase inhibitors (eg, 
tazobactam, sulbactam, clavulanic acid, avibactam), or metronidazole.
NOTE: A history of mild rash to any of these agents is not a contraindication to 
enrollment.
5.
Has an IAI within the past 1 year prior to randomization known to be caused by a 
pathogen 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).
7.
Has received potentially therapeutic antibacterial therapy (eg, with gram-negative 
activity) for a duration more than 24 hours during the 48 hours preceding the first 
dose of study treatment, unless the subject is considered to be failing antibiotic 
therapy for cIAI.
NOTE: A subject considered to be failing a previous antibiotic regimen must meet 
all of the following criteria:
a) Has received the systemic antibacterial treatment for at least 48 hours 
b) Has clinical and operative or radiographic findings clearly indicating ongoing 
infection 
c) Has planned operative intervention no more than 24 hours after first dose of 
study treatment 
d) Has not received any further nonstudy antibiotics postoperatively
8.
Has any of the following:
a) Intractable cIAI that the investigator anticipates would require more than 14 
days of study treatment
b) Abdominal wall abscess
c) Small bowel obstruction 
d) Ischemic bowel disease without perforation 
e) Traumatic bowel perforation with surgery within 12 hours of perforation
f)
Perforation of gastroduodenal ulcers requiring surgery within 24 hours of 
perforation (these are considered situations of peritoneal soiling before the 
infection has become established) 
g) Suspected uncomplicated intra-abdominal infection (eg, cholecystitis without 
rupture or extension beyond the gallbladder wall) 
h) Acute suppurative cholangitis
i)
Infected necrotizing pancreatitis 
 
 
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j)
Pancreatic abscess
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 [12] 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:
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) Probenecid
c) Valproic acid or divalproex sodium
d) Disulfiram
e) Ergot derivatives
f)
Ethanol-containing medications
g) Nonstudy systemic (IV or oral) antibacterial treatments
NOTE: Subjects who require empiric enterococcal coverage for the index cIAI 
may receive concomitant therapy with an enterococcal antibiotic with activity 
limited to gram-positive coverage (eg, vancomycin, daptomycin, teicoplanin, 
linezolid). One dose of prophylactic antibiotic with gram-negative activity is 
allowed.
Subjects who require empiric antifungal coverage for the index cIAI may 
receive concomitant antifungal coverage with an azole, echinocandin, or 
polyene antifungal as chosen by the investigator based on local standard of care.
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 acquired immune 
deficiency syndrome (AIDS), hematological malignancy, or bone marrow 
transplantation, or is receiving immunosuppressive therapy including cancer 
chemotherapy, medications for prevention of organ transplantation rejection, or 
 
 
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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.
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 6 and Table 7.
Intravenous Trial Treatments
The IV treatment regimens to be used in this trial are outlined in Table 6.
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 5 days and a maximum of 14 
days.
NOTE: In Ukraine, enrollment will be limited to subjects 2 years to < 18 years of age 
(Groups 1-3). Study treatments for Groups 4 and 5 are not applicable at Ukrainian sites.
Table 6
Intravenous Trial Treatments
Drug
Dose/Potency
Dose 
Frequencya
Route of 
Administrationb
Treatment 
Periodb
Use
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
5-14 days
Experimental
Metronidazole
Metronidazole 
10 mg/kg 
(maximum dose 
1.5 g/day)
Every 
8 hours
IV
5-14 days
Adjunctive
Meropenem 
and placebo for 
metronidazole
Meropenem 
20 mg/kg 
(maximum 1 g/dose)
Every 
8 hours
IV
5-14 days
Active
comparator
 
 
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Drug
Dose/Potency
Dose 
Frequencya
Route of 
Administrationb
Treatment 
Periodb
Use
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
5-14 days
Experimental
Metronidazole
Metronidazole 
10 mg/kg 
(maximum dose 
1.5 g/day)
Every 
8 hours
IV
5-14 days
Adjunctive
Meropenem 
and placebo for 
metronidazole
Meropenem 
20 mg/kg 
(maximum 1 g/dose)
Every 
8 hours
IV
5-14 days
Active
comparator
Group 3 (2 to <6 years [n≥57 combined with same age group in MK-7625A-034])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
5-14 days
Experimental
Metronidazole
Metronidazole 
10 mg/kg 
(maximum dose 
1.5 g/day)
Every 
8 hours
IV
5-14 days
Adjunctive
Meropenem 
and placebo for 
metronidazole
Meropenem
20 mg/kg 
(maximum 1 g/dose)
Every 
8 hours
IV
5-14 days
Active
comparator
Group 4 (3 months to <2 years [n≥24 combined with same age group in MK-7625A-034])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
5-14 days
Experimental
Metronidazole
Metronidazole 
10 mg/kg 
(maximum dose 
1.5 g/day)
Every 
8 hours
IV
5-14 days
Adjunctive
 
 
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Drug
Dose/Potency
Dose 
Frequencya
Route of 
Administrationb
Treatment 
Periodb
Use
Meropenem 
and placebo for 
metronidazole
Meropenem 
20 mg/kg 
(maximum 1 g/dose)
Every 
8 hours
IV
5-14 days
Active
comparator
Group 5 (Birthd to <3 months [n≥21 combined with same age group in MK-7625A-034])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
5-14 days
Experimental
Metronidazole
Subjects >28 days of 
age:
Metronidazole 
10 mg/kg every 
8 hours (maximum 
dose 1.5 g/day)
For subjects ≤28 
days of age, the 
suggested dosing 
regimen is listed 
below; however,
other site-specific 
standard of care 
metronidazole 
dosing may be used 
at the investigator’s 
discretion.
Subjects ≤28 days of 
age and ≤2 kg:
Metronidazole 
15 mg/kg loading 
dose, then 
7.5 mg/kg/dose 
every 12 hours
Subjects ≤28 days of 
age and >2 kg:
Metronidazole 
15 mg/kg loading 
dose, 10 mg/kg dose 
every 8 hours
Every 
8-12 hoursf
IV
5-14 days
Adjunctive
Meropenem 
and placebo for 
metronidazolef
Meropenem 
20 mg/kg 
(maximum
1 g/dose)e
Every 
8 hours
IV
5-14 days
Active
comparator
 
 
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Drug
Dose/Potency
Dose 
Frequencya
Route of 
Administrationb
Treatment 
Periodb
Use
IV = intravenous
a
Each dose of ceftolozane/tazobactam or metronidazole or meropenem or placebo is administered as a 60-minute 
(±10 minutes) infusion. Ceftolozane/tazobactam plus metronidazole or meropenem plus placebo 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 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 5 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.
f
Subjects 7 to 28 days of age who receive metronidazole with a frequency other than every 8 hours must receive 
placebo at the same frequency to maintain blinding.
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 5 days 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 7 lists recommended options for oral step-down therapy.
Table 7
Recommended Oral Step-down Therapy Options
Antibiotic or Antibiotic Classa
β-lactam/β-lactamase inhibitor combination
Second or third generation cephalosporin in combination with metronidazole
Quinolone (if ciprofloxacin or levofloxacin are chosen, it should be used in combination with 
metronidazole)
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.
 
 
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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 6 and Table 7 above 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)
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 plus metronidazole or meropenem plus placebo 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.
 
 
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*Subjects who are 7-28 days old may be dosed every 12 hours with metronidazole. Please 
refer to Table 6 in Section 5.2.1 – Intravenous Trial Treatments for metronidazole dosing 
recommendations in this age group.
Trial Blinding 
A double-blinding technique with in-house blinding will be used.  Ceftolozane/tazobactam 
plus metronidazole and meropenem plus placebo 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 plus metronidazole or 
meropenem plus placebo, 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.
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.
 
 
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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

Disulfiram

Ergot derivatives

Ethanol-containing medications

Nonstudy systemic (IV or oral) antibacterial treatments
NOTE: Subjects who require empiric enterococcal coverage for the index cIAI may 
receive concomitant therapy with an enterococcal antibiotic with activity limited to 
gram-positive coverage (eg, vancomycin, daptomycin, teicoplanin, linezolid). One 
dose of prophylactic antibiotic with gram-negative activity is allowed.
Subjects who require empiric antifungal coverage for the index cIAI may receive 
concomitant antifungal coverage with an azole, echinocandin or polyene antifungal as 
chosen by the investigator based on local standard of care.
The following medications are permitted, although their efficacy and safety should be 
clinically monitored and/or serum levels followed with appropriate dosage adjustments as 
necessary at the initiation of study drug, periodically during treatment, and after 
discontinuation of study drug:

Lithium

Phenytoin

Warfarin

Carbamazepine 

Medications resulting in prolonged QT interval
All other concomitant medications necessary for the health and well-being of the subject are 
permitted.
 
 
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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 or caffeine 
consumption, tobacco use, or activity. Subjects should not consume alcohol while on IV 
study treatment due to potential interaction with metronidazole.
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.
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
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 [12] or requirement 
for peritoneal dialysis, hemodialysis, or hemofiltration (required for IV study treatment 
only).
 
 
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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-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).
 
 
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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 (5 to 14 days)a
Follow-up
Visit Number:
1
2
3 to 16
17
18
19
20
21
Visit Title:
Screeningb
Randomizationb
IV Clinical 
Assessmentsa,b
EOIVc
(all 
subjects)
Oral Clinical 
Assessmentd,e
(only for IV to 
oral switch)
EOTd
(only for IV 
to oral 
switch)
TOC
(all subjects)
LFUf
(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
7 to 14 days 
after final 
dose
21 to 28 
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 IV ceftolozane/tazobactam + 
metronidazole or IV meropenem + 
placebo every 8 h
X
X
Standard of care oral step-down therapya
X
Clinical Procedures/Assessments
Body weight
X
Xg,h
Xg,h
Xg
Xg,h
Xg
Height
X
Vital signs (heart rate, respiratory rate, 
blood pressure, and temperature)
X
X
X
X
X
X
X
Xg,i
Full physical examination
X
Directed physical examination
Xj
X
X
X
X
Xg,i
Record surgical wound examinationg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg,i
Abdominal sign/symptom assessment
X
X
X
X
X
X
X
Xg,i
Record summary of operative procedures 
(as indicated/done)
X
X
X
X
X
X
X
 
 
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Trial Period:
Screening
Treatment (5 to 14 days)a
Follow-up
Visit Number:
1
2
3 to 16
17
18
19
20
21
Visit Title:
Screeningb
Randomizationb
IV Clinical 
Assessmentsa,b
EOIVc
(all 
subjects)
Oral Clinical 
Assessmentd,e
(only for IV to 
oral switch)
EOTd
(only for IV 
to oral 
switch)
TOC
(all subjects)
LFUf
(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
7 to 14 days 
after final 
dose
21 to 28 
days after 
final dose
Record radiological examination
Xg
Xg
Xg
Xg
Xg
Xg
Xg
Xg
AE monitoringk
X
X
X
X
X
X
X
Assess clinical outcome
X
X
X
Laboratory Procedures/Assessments
Blood for hematology and chemistry 
safety evaluations
X
Xj
Xl
X
Xl
X
Xg,i
Coombs test (direct)
X
X
Serum pregnancy testm
Xm
Xm
Assessment of CrCL
X
Xg
Xg
Xg
Xg
Intra-abdominal sample for culture and 
susceptibility testing
Xn
Xg
Xg
Xg
Xg
Xg
Blood for culture and susceptibility 
testingg
Xg
Xg
Xg
Blood for PK analyses (Day 3 only [after 
≥6 doses of IV study treatment])o
Xo
 
 
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AE = adverse event; 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 5 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 within <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 an EOT Visit.
d
Only for subjects who are switched to oral step-down therapy.
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 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 the EOIV or EOT Visit, blood samples for these evaluations are not 
required at the visit.
m
Female subjects of childbearing potential only. A urine pregnancy test instead of a serum pregnancy test may be performed at the TOC Visit, if deemed clinically appropriate 
by the investigator.
n
Baseline intra-abdominal specimen collection in compliance with Section 7.1.3.4 – Intra-abdominal Samples for Culture. Subjects who are enrolled preprocedure should have 
a sample obtained during the interventional procedure performed to comply with Section 7.1.3.4.
o
Blood samples for ceftolozane, tazobactam, and tazobactam M1 concentration assays will be collected from all subjects over one 8-h dosing period on Day 3 of the treatment 
period after administration of at least 6 doses of IV study treatment (see Section 7.1.3.6 – 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 hours 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 cIAI episodes or conditions 
that may predispose a subject to the development of cIAI 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.
Surgical Wound Examination
Surgical wound examination is performed as clinically indicated and noted in Section 6.0 –
Trial Flow Chart to assess signs of infection such as skin erythema, induration, tenderness, 
warmth, fluctuance, swelling, and wound pain. If signs of infection are present, findings will 
be recorded and categorized as present, absent, or unable to assess. If wound discharge is 
present, the nature of the discharge (nonpurulent or purulent) will be assessed. This 
assessment should ideally be performed at the same time each day.
Abdominal Sign and Symptom Assessment
The abdominal signs and symptoms of cIAI (see Section 5.1.2 - Subject Inclusion Criteria, 
Criterion 4) will be evaluated and graded as absent, present, or unable to assess at the visits 
specified in Section 6.0 – Trial Flow Chart. The signs and symptoms of cIAI (eg, fever, 
leukocytosis, hypotension, abdominal pain, nausea/vomiting, anorexia, abdominal mass on 
clinical examination, and altered mental status) will be assessed at Screening by clinical 
examination of the abdomen and noted as absent, present, or not able to assess/not 
performed.
At visits after Screening, the investigator will assess each observed sign or symptom 
according to the categories above. The clinical signs and symptoms of cIAI are not 
considered AEs, unless a sign or symptom qualifies as an SAE.
 
 
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Summary of Operative Procedures
A summary of interventional operative procedures to treat cIAI will be recorded. The 
anatomic site of infection, the presence of one or more abscesses, the extent of peritonitis, 
and the etiological mechanism (eg, trauma, postoperative, or spontaneous rupture) must be 
recorded. Copies of all surgical reports must be retained for review during monitoring visits.
Radiological Examination
Specific radiographic examinations are not required for this study unless the subject is 
enrolled preoperatively. Radiological examinations should only be performed as required for 
routine clinical management. Radiological evaluations might include plain abdominal 
radiograph, computed tomography (CT) scan, ultrasound, and/or magnetic resonance 
imaging (MRI) scan, with or without contrast. The results of any such studies should be 
recorded. Copies of all interventional radiological reports and diagnostic study reports must 
be retained for review during monitoring visits.
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.
Assessment of Microbiological Outcome
All microbiological outcomes will be assessed by the Sponsor based on culture results, as 
defined in Section 4.2.3.2 – Rationale for Efficacy Endpoints. Investigators are not 
responsible for assessment of 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.
 
 
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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.
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 8). 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.
Blood samples for laboratory safety evaluations will be collected without regard to meals or 
study treatment.
Table 8
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.
 
 
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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 performed 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 [12], 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.
Intra-abdominal Samples for Culture
The investigator or qualified designee will obtain intra-abdominal specimens at the visits 
specified in Section 6.0 – Trial Flow Chart for culture of aerobic and anaerobic organisms 
during the interventional procedure. Specimens should be collected at the beginning of the 
interventional procedure prior to debridement, removal, or disinfection of the primary site of 
infection. Aspirates (collected with a needle or syringe) or tissue or biopsy samples are 
recommended, and swabs of purulent material are discouraged. Specimens should not be 
obtained from in situ abdominal drains. 
Thereafter, specimens for culture are to be obtained from the site of infection, if clinically 
indicated (eg, if re-intervention is required, collection during the additional surgery in 
subjects with clinical failure) to evaluate the microbiological assessment. Specimens should 
not be obtained from in situ abdominal drains. Culture of the intra-abdominal specimen,
isolation of pathogen(s), initial identification of pathogen(s), and susceptibility testing will be 
conducted by the local laboratory. The result of culture and initial identification of 
pathogen(s) at the local laboratory should be recorded in the source document and eCRF. The 
sites should 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.
 
 
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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.
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.
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.
 
 
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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 AEs that 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.
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 
pre-specified 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.
 
 
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Subjects whose treatment assignment has been unblinded by the investigator/delegate and/or 
nonstudy 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. 
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 –
 
 
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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.
Clinical Assessment Visits on Intravenous Study Treatment
Clinical Assessment Visits on IV study treatment occur daily on Day 2 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.
 
 
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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.
Test of Cure Visit
The TOC Visit occurs in all subjects 7 to 14 days after the final dose of study treatment (IV 
or oral).
Last Follow-up Visit
The LFU Visit occurs in all subjects 21 to 28 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 
 
 
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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, 
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, 21 to 28 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, meropenem, and 
metronidazole. 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 
 
 
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(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 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 9 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.
 
 
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For the time period beginning at treatment allocation/randomization through the last trial 
evaluation (Last Follow-up visit, 21 to 28 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 
found in the Investigator Trial File Binder (or equivalent). All serious adverse events 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 serious adverse events 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, 21 to 28 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 
 
 
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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 9. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 9 for instructions in evaluating adverse events.
 
 
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Table 9
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) 
plus 
metronidazole 
versus 
meropenem in pediatric subjects with complicated intra-abdominal 
infections.
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 plus metronidazole or IV 
meropenem plus placebo, respectively. The total duration of study 
treatment will be a minimum of 5 days to a maximum of 14 days. 
Randomization will be stratified by age group. See Table 6
for target 
enrollments and IV dosage regimens for each age group.
Analysis Populations
Safety: All Subjects as Treated (ASaT) Population
Pharmacokinetics: PK Population
Efficacy: Modified Intent-to-Treat (MITT), 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 [20]
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 [20], 
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 cUTI (MK-
7625A-034). Additional details are available in the external DMC charter.
Multiplicity
There will be no adjustment for multiplicity in this estimation trial.
 
 
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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 plus metronidazole arm and approximately 60 
subjects in the meropenem plus placebo arm. The estimated differences and 
95% CIs for event rate under various scenarios for the combined trials are 
presented in Table 14 . 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 – Objective(s) & 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 
postrandomization 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 
 
 
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phosphatase ≤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 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 success rate at the EOT and TOC Visits, defined as the 
proportion of subjects in the analysis population who have microbiological 
eradication or presumed eradication of all baseline pathogens.
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. 
 
 
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
Per-subject microbiological success rate at the EOIV Visit, defined as the proportion 
of subjects in the analysis population who have a microbiological outcome of 
eradication or presumed eradication of all baseline pathogens.

Per-pathogen microbiological success rate at the EOIV, EOT, and TOC Visits, 
defined as the proportion of baseline pathogens that have an outcome of 
microbiological eradication or presumed 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.
The percentage of subjects with superinfection or new infection will also be estimated.
Emergent infection categories are defined in Table 5 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 10. Additional details about 
evaluability criteria for each efficacy analysis population will be provided in an evaluability 
guideline document.
 
 
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Table 10
Efficacy Analysis Populations
Populationa
Definitiona
Modified Intent-to-Treat 
(MITT)
The MITT population will consist of all randomized subjects who receive any 
amount of study treatment. Subjects will be categorized based on the IV study 
treatment that subjects were randomized to, irrespective of what treatment 
they actually received.
Microbiological Modified 
Intent-to-Treat (mMITT)
The mMITT population will be the subset of subjects in the MITT population 
who have at least 1 pathogen identified from the baseline intra-abdominal 
culture, regardless of susceptibility to study treatment. 
Clinically Evaluable (CE)
The CE population will be the subset of subjects in the MITT population who 
adhere to trial procedures and have a clinical outcome at the visit of interest. 
An interpretable 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 at least 1 causative pathogen identified from the baseline intra-
abdominal culture.
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 11). 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 [20], 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 
 
 
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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.
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.
Table 11
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
 
 
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Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
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 MITT and mMITT population and a DAO approach for the 
ME and CE populations (Table 12), with the following definitions:

For the analysis of clinical response in the MITT and microbiological response in the 
mMITT population, subjects with missing clinical response or microbiological 
response (eg, indeterminate) will be considered treatment failures.

For the analyses in the ME or CE population, subjects with a missing clinical 
response or microbiological response (eg, indeterminate) will be excluded from the 
population.

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.

A missing microbiological outcome at the TOC Visit will be considered 
indeterminate if the clinical outcome at the TOC Visit is indeterminate as well. 
Microbiological response will be presumed from clinical response when there is no 
suitable intra-abdominal specimen to culture on/after the EOT/EOIV Visit through 
the TOC Visit.
The M&N statistical method [20] with data stratified by age group will be used to make 
between-group comparisons for binary outcomes (Table 13), but no tests of hypotheses are 
planned in this estimation trial.
 
 
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Table 12
Analysis Strategy for Efficacy Variables
Endpoint/Variablea
(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
MITT
Treatment Failure 
S
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
MITT
Treatment Failure 
S
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
CE = clinically evaluable; EOIV = End of IV Treatment; EOT = End of Treatment; ME = Microbiologically 
Evaluable; MITT = Modified Intent-to-Treat; mMITT = microbiological Modified Intent-to-Treat; TOC = Test
of Cure
a
The Miettinen and Nurminen statistical method [20] will be used for all analyses and will include
stratification by age.
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.
Table 13
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
 
 
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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, 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 

Baseline signs and symptoms of cIAI

Primary site of infection

Anatomic site of infection

Presence of abscess

Number of abscesses (single, multiple)

Presence of peritonitis (yes, no)

Peritonitis type

Localized complicated appendicitis (yes, no)

Etiological mechanism

Failure of prior therapy

Procedure type

Wound closure

All abscesses confirmed drained (yes, no)

Site of infection (appendix, nonappendix) 
 
 
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
Prior antibiotic use

Presence of bacteremia at baseline (yes, no)

Number of baseline pathogens (polymicrobial, monomicrobial)

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.
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 cUTI (MK-7625A-034). 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 plus metronidazole treatment arm and an expected 60 subjects in the 
meropenem plus placebo treatment arm. With a sample size of 180 ceftolozane/tazobactam-
treated subjects in both this trial and the tandem cUTI trial (MK-7625A-034) (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 14
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 [20].
 
 
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Table 14
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

Duration of IV study treatment

Primary site of infection (bowel [small or large], other site of infection)

Etiological mechanism (nosocomial infection [postoperative/hospital acquired 
infection], community-acquired infection [trauma, spontaneous rupture, malignancy 
or other])

Number of abscesses (single, multiple)

Peritonitis type (local, diffuse)

Procedure type (percutaneous aspiration, laparoscopy, laparotomy, other)

Prior antibiotic use (yes, no)

Site of infection (appendix, nonappendix)

Baseline bacteremia (yes, no)
 
 
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
Number of baseline pathogens (polymicrobial, monomicrobial)

Pathogen MIC (susceptible, intermediate, resistant as defined in the SAP) and 
pathogen classification

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.  
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.
Clinical Supplies will be provided by the Sponsor as summarized in Table 15.
 
 
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Table 15
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
1
Metronidazole-IV
Cohort 
dose
0.5 g
0.5 g/
100-mL 
bag or 
0.5 g/vial
Commercial 
metronidazole
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 
Metronidazole 0.5 g
0.5 g/100-mL bag or 
0.5 g/vial
Provided centrally by the Sponsor 
Meropenem 1 g
1-g lyophilized vial
Provided centrally by the Sponsor 
Placebo
IV
Site sourced
All supplies indicated in Table 15 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 15 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 
 
 
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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.
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.
 
 
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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 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.
 
 
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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.
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.
 
 
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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 
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.
 
 
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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 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.
 
 
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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 
 
 
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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.
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.
11.0 LIST OF REFERENCES
[1]
Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJC, Baron EJ, 
et al. Diagnosis and management of complicated intra-abdominal infection in 
adults and children:  guidelines by the surgical infection society and the 
infectious diseases society of America. Clin Infect Dis 2010;50:133-64.
[2]
Thompson AE, Marshall JC, Opal SM. Intraabdominal infections in infants 
and children: descriptions and definitions. Pediatr Crit Care Med. 2005 
May;6(3 Suppl):S30-5.
[3]
Claud EC. Neonatal necrotizing enterocolitis -inflammation and intestinal 
immaturity. Antiinflamm Antiallergy Agents Med Chem. 2009 Sep;8(3):248-
259.
[4]
Newman N, Wattad E, Greenberg D, Peled N, Cohen Z, Leibovitz E. 
Community-acquired complicated intra-abdominal infections in children 
hospitalized during 1995-2004 at a paediatric surgery department. Scand J 
Infect Dis. 2009;41(10):720-6.
[5]
Nance ML, Adamson WT, Hedrick HL. Appendicitis in the young child: a 
continuing diagnostic challenge. Pediatr Emerg Care. 2000 Jun;16(3):160-2.
[6]
Sartelli M, Catena F, Coccolini F, Pinna AD. Antimicrobial management of 
intra-abdominal infections: literature's guidelines. World J Gastroenterol. 2012 
Mar 7;18(9):865-71.
[7]
Brook I. Bacterial studies of peritoneal cavity and postoperative surgical 
wound drainage following perforated appendix in children. Ann Surg. 1980 
Aug;192(2):208-12.
[8]
Dupont H. The empiric treatment of nosocomial intra-abdominal infections. 
Int J Infect Dis. 2007 May;11 Suppl 1:S1-6.
[9]
Spirt MJ. Complicated intra-abdominal infections: a focus on appendicitis and 
diverticulitis. Postgrad Med. 2010 Jan;122(1):39-51.
 
 
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[10]
Goldin AB, Sawin RS, Garrison MM, Zerr DM, Christakis DA. 
Aminoglycoside-based triple-antibiotic therapy versus monotherapy for 
children with ruptured appendicitis. Pediatrics. 2007 May;119(5):905-11.
[11]
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.
[12]
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.
[13]
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
[14]
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.
[15]
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.
[16]
Pickering LK, Baker CJ, Kimberlin DW, Long SS. Red Book: 2012 Report of 
the committee on infectious diseases. Clostridium difficile. 29 ed. Elk Grove 
Village: American Academy of Pediatrics, 2012:285-7.
[17]
U.S. Prescribing Information: MERREM I.V. (meropenem for Injection): 
2013.
[18]
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.
[19]
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.
 
 
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[20]
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 16.
Table 16
Approximate Blood Volumes Collected by Trial Visit
Approximate Blood Sample Volume (mL)
Trial Period:
Screening
Treatment (5 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)
LFUa
(all 
subjects)
Safety 
hematology and 
chemistry, serum 
creatinine
3.5
3.5b
3.5
3.5
3.5
3.5
3.5c,d
Coombs test 
(direct)
1.0
0
1.0
0
0
0
0
Serum pregnancy 
teste
3.0
0
0
0
0
3.0e
0
Blood for culture
7.0c
7.0c,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 childbearing potential only. A urine pregnancy test instead of a serum pregnancy test may be 
performed 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 7.1.3.6 – 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
AIDS
Acquired Immune Deficiency Syndrome
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
Cmax
Maximum observed concentration
CrCL
Creatinine clearance
CRF
Case Report Form
CSR
Clinical study report
Ct
Threshold drug concentration
CT
Computed tomography
cUTI
Complicated urinary tract infection
DAO
Data as observed
DMC
Data Monitoring Committee
eCRF
Electronic case report form
 
 
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Abbreviation or 
Term
Definition
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
GI
Gastrointestinal
Hg
Mercury (for BP, mm Hg)
HIV
Human immunodeficiency virus
IAI
Intra-abdominal infection
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IDSA
Infectious Disease Society of America
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
MITT
Modified Intent-to-Treat
mMITT
Microbiological Modified Intent-to-Treat
MRI
Magnetic resonance imaging
 
 
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Abbreviation or 
Term
Definition
MRSA
Methicillin-resistant Staphylococcus aureus
NEC
Necrotizing enterocolitis
NP
Nosocomial pneumonia
OTC
Over the counter
PIN
Personal identification number
PK
Pharmacokinetic(s)
PTA
Probability of target attainment
Q
Intercompartmental clearance
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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