Clinical trial NCT04126031
Conditions: Gram-negative Bacterial Infection
Keywords: Gram-negative, ceftazidime-avibactam, neonate, infant
Sponsor: Pfizer
Start date: 2020-01-14; Completion date: 2022-12-30
Enrollment: 48 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study will assess the pharmacokinetics, safety, and tolerability of single and multiple doses of intravenous ceftazidime-avibactam in hospitalized infants and neonates from 26 weeks gestation to 3 months of age. In Part A of the study all patients will receive a single dose of ceftazidime-avibactam. In Part B all patients will received multiple doses of ceftazidime-avibactam. Efficacy will be assessed in the infants and neonates receiving multiple doses of ceftazidime-avibactam.

Detailed description:
This is a 2-part, Phase 2a, non-randomized, open-label multicenter, multinational study of intravenous ceftazidime-avibactam in hospitalized neonates and infants with suspected or confirmed bacterial infection. In Part A of the study, patients already receiving intravenous antibacterial therapy with another antibiotic will receive a single intravenous dose of ceftazidime-avibactam followed by observation for 48 hours and a Late Follow-Up assessment 4-5 weeks later. In Part B of the study, patients with suspected or confirmed Gram-negative bacterial infections requiring intravenous antibacterial therapy will receive multiple doses of intravenous ceftazidime-avibactam for up to 14 days. At the discretion of the investigator, patients may also receive other antibiotics if the infection is suspected to include Gram-positive bacteria, multi-drug resistant Gram-negative bacteria, or anaerobic bacteria. At the discretion of the investigator, patients may be switched to oral therapy or outpatient parenteral antimicrobial therapy with an alternative antibiotic after receiving intravenous ceftazidime-avibactam for at least 48 yhours. Clinical outcomes will be assessed at the End of Intravenous (EOIV) treatment with ceftazidime-avibactam, the End-of-Therapy (EOT), the Test-of-Cure (TOC) at 7-14 days after the last study therapy and at a Late Follow-Up (LFU) visit, 28-55 days after the last dose of ceftazidime-avibactam. Safety assessments will occur throughout the study. Ceftazidime-avibactam blood levels will be assessed during the first 12 hours after the single dose of ceftazidime-avibactam in Part A and during 12 hours after at least 3 consecutive doses of ceftazidime-avibactam in Part B.

Arms: arm 1: Single dose pharmacokinetics. This arm will include three age cohorts. arm 2: Multi-dose pharmacokinetics. This arm will include three age cohorts.
Interventions: intervention 1: Part A: Single Dose Ceftazidime-Avibactam, Cohorts 1-3 intervention 2: Part B: Multiple-dose Ceftazidime-Avibactam, Cohorts 1-3
Intervention descriptions: intervention 1: Single intravenous infusion of ceftazidime-avibactam over 2 hours intervention 2: Multiple intravenous infusions of ceftazidime-avibactam over 2 hours, repeated every 8 hours up to 14 days

Protocol documents:
Prot_000.pdf: 
Ceftazidime-Avibactam (CAZ-AVI)
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A PHASE 2A, 2-PART, OPEN-LABEL, NON-RANDOMIZED, MULTICENTER, 
SINGLE AND MULTIPLE DOSE TRIAL TO EVALUATE PHARMACOKINETICS,
SAFETY AND TOLERABILITY OF CEFTAZIDIME AND AVIBACTAM IN 
NEONATES AND INFANTS FROM BIRTH TO LESS THAN 3 MONTHS OF AGE 
WITH SUSPECTED OR CONFIRMED INFECTIONS DUE TO GRAM-NEGATIVE 
PATHOGENS REQUIRING INTRAVENOUS ANTIBIOTIC TREATMENT
Investigational Product Number:
PF-06947386
Investigational Product Name:
Zavicefta (Ceftazidime-Avibactam)
United States (US) Investigational New 
Drug (IND) Number:
101,307
European Clinical Trials Database 
(EudraCT) Number:
2018-002800-16
Protocol Number:
C3591024
Phase:
2a
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.


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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1 
27 June 2019
In addition to minor administrative changes and clarifications, 
protocol amendment 1 includes the following:
Throughout the document, changes were made to recording of 
temperature measurement post-baseline. Recording of 
temperature will not be performed postdose as originally
indicated. 
The protocol summary, the introduction and study design have 
been updated to include the CAZ-AVI pediatric approval in 
children from 3 months of age and older in 2019 received in the 
US for the treatment of cIAI (when combined with 
metronidazole), and for the treatment of cUTI. Text now also 
has been updated to show that CAZ-AVI has received regulatory 
approval in 51 countries worldwide. 
Text has been updated to show that this study is planned to be 
performed at approximately 40 sites and 15 countries in the US, 
Europe, and Asia.
Part B Cohort 3 enrollment sequence has been revised as 
requested by the EMA Pediatric Committee (PDCO) on
19 Oct 2018.  
The purpose of this request was to ensure that enrollment of 
subjects in Part B Cohort 3, who represent the most vulnerable 
population based on their age (Pre term neonates (GA ≥26 to 
<37 weeks) from birth to ≤28 days), is initiated only after data 
from the other cohorts is first evaluated.
PK analyses will be performed as described in Section 9.2 
Pharmacokinetic Analysis so the description of PK endpoints in 
Section 2 was simplified. Another secondary endpoint for Part B 
(emergent infections) has been added. Text was updated in 
Sections 7.1.1 and 9.2 to use ‘nominal sampling time’ uniformly 
throughout the protocol in the description of the pharmacokinetic 
endpoint, for consistency with the endpoint description 
Section 2.
Inclusion criteria text in Section 4.1.1 for all subjects 
(criterion 3a) has been revised to clarify that <3 months is
<89 days.
It has also been clarified in Section 4.1.3 (criterion 2) that 
subjects in Part B only must meet at least 1 clinical and 
1 laboratory criterion or meet at least 2 of the clinical criteria to 
be enrolled. 


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Version Date
Summary of Changes and Rationale
The Table 2 title in Section 5.5 was simplified and the term 
“dose” has been revised to “weight-based dose”. The Infusion 
Volume in Table 2, Section 5.5 and the requirement for using 
aseptic technique for study drug preparation and administration
in Section 5.4.2 has also been revised to match the 
Investigational Product Manual.  
The following sentence has been added to the Concomitant 
Treatments section: “In Part A, the use of any other antibiotics is 
permitted, including other antibiotics combined with beta 
lactamase inhibitors. In Part B, the use of antibiotics combined 
with other beta lactamase inhibitors is prohibited, including
combinations with the beta lactamase inhibitors sulbactam, 
tazobactam, clavulanate, and any new beta lactamase inhibitors 
which become available during the course of the study.”
Custom blue top tubes will be used to collect plasma for PK 
analysis instead of the standard sodium fluoride/potassium 
oxalate grey-top tube.
Additional details have been provided regarding sources of blood 
for PK blood samples, including multi-lumen catheters where 
one lumen is used to infuse CAZ-AVI.
The collection time of the first blood PK samples has been 
changed to indicate that it should be collected anytime within 
15 minutes after stopping CAZ-AVI infusion.  
The paragraph about PK sample collection in Part B has been
revised to clarify that in Part B, PK samples will be collected 
after at least 3 consecutive doses of CAZ-AVI have been infused. 
The definition of PK sampling times relative to the start of the 
infusion has been added to explain the nominal times for PK 
samples as specified in the CRF.
Additional possible uses specified for left over plasma, if any, 
not used for PK assessments.
It has been clarified that in Part B, the PK analysis set consist of 
all subjects with at least 3 consecutive doses of CAZ-AVI in 
Part B with at least 1 ceftazidime and/or avibactam plasma PK 
measurement available. 
In the efficacy analysis Section 9.4, the definition of ITT, a 
sentence detailing the summary of all-cause mortality, a 
clarification that clinical outcomes will be summarized for all 
3 analysis sets (ITT, MITT and micro ITT), and a clarification 


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Summary of Changes and Rationale
that microbiological response will be summarized only for the 
micro ITT, have been added.
A Per-subject microbiological Response table (Table 7) has been 
added to section 9.4.2 as well as the definition of emergent 
infections (Table 8).
Appendix 2 was added to clarify the determination of pre-term 
infant eligibility for Cohort 1 according to corrected age.  The 
original Appendix 2 was moved to Appendix 3.
Original 
protocol
11 July 2018
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs/ethics committees 
(ECs). 


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
LIST OF FIGURES .................................................................................................................10
APPENDICES .........................................................................................................................10
PROTOCOL SUMMARY.......................................................................................................11
SCHEDULE OF ACTIVITIES................................................................................................15
1. INTRODUCTION ...............................................................................................................20
1.1. Mechanism of Action/Indication.............................................................................20
1.2. Background .............................................................................................................21
1.3. Rationale for Conducting This Study......................................................................21
1.4. Dose Rationale ........................................................................................................22
1.5. Benefit/Risk and Ethical Assessment......................................................................23
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................25
3. STUDY DESIGN.................................................................................................................25
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................28
4.1. Inclusion Criteria.....................................................................................................28
4.1.1. Inclusion Criteria for All Subjects..............................................................28
4.1.2. Inclusion Criteria for Part A Subjects Only................................................29
4.1.3. Inclusion Criteria for Part B Subjects Only................................................29
4.2. Exclusion Criteria....................................................................................................30
4.2.1. Exclusion Criteria for All Subjects.............................................................30
4.2.2. Exclusion Criteria for Part A Subjects Only...............................................31
4.2.3. Exclusion Criteria for Part B Subjects Only...............................................31
4.3. Randomization Criteria ...........................................................................................32
4.4. Cohort Enrollment Sequence ..................................................................................32
4.5. Procedures for Handling Incorrectly Enrolled Subjects..........................................32
4.6. Sponsor’s Qualified Medical Personnel..................................................................32
5. STUDY TREATMENTS.....................................................................................................33
5.1. Allocation to Treatment ..........................................................................................33
5.2. Breaking the Blind ..................................................................................................33
5.3. Subject Compliance.................................................................................................33
5.4. Investigational Product Supplies.............................................................................34


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5.4.1. Dosage Form(s) and Packaging..................................................................34
5.4.2. Preparation and Dispensing........................................................................34
5.5. Administration (Dose and Treatment Regimen) .....................................................35
5.5.1. Part A..........................................................................................................35
5.5.2. Part B ..........................................................................................................35
5.6. Investigational Product Storage ..............................................................................36
5.7. Investigational Product Accountability...................................................................37
5.7.1. Destruction of Investigational Product Supplies ........................................37
5.8. Oral Switch Therapy ...............................................................................................37
5.9. Intravenous Switch Therapy....................................................................................38
5.10. Concomitant Treatment(s).....................................................................................38
6. STUDY PROCEDURES .....................................................................................................39
6.1. Screening and Enrollment .......................................................................................39
6.1.1. Visit 1: Eligibility/Screening Procedures (Day -1 to 1)..............................39
6.1.1.1. Clinical Assessments.................................................................40
6.1.1.2. Laboratory Assessments............................................................41
6.1.1.3. Microbiological Assessments (Part B Only).............................41
6.2. Study Period ............................................................................................................42
6.2.1. Visit 2, Study Day 1....................................................................................42
6.2.1.1. Study Therapy Administration..................................................42
6.2.1.2. Clinical Assessments.................................................................42
6.2.1.3. Laboratory Assessments............................................................43
6.2.1.4. Microbiological Assessments (Part B Only).............................43
6.2.1.5. PK Procedures – Part A Only....................................................43
6.2.2. Visit 3, Study Day 2: Part A Only..............................................................44
6.2.2.1. Clinical Assessments.................................................................44
6.2.2.2. Laboratory Assessments............................................................44
6.2.3. Visit 4, Study Day 3: Part A Only..............................................................44
6.2.3.1. Clinical Assessments.................................................................44
6.2.3.2. Laboratory Assessments............................................................45
6.2.4. Visits 3-15, Study Days 2-14: Part B Only.................................................45
6.2.4.1. Study Therapy Administration..................................................45


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6.2.4.2. Clinical Assessments.................................................................45
6.2.4.3. Laboratory Assessments............................................................46
6.2.4.4. Microbiological Assessments....................................................46
6.2.4.5. PK Procedures...........................................................................47
6.2.5. End of IV (EOIV): Part B Only..................................................................47
6.2.5.1. Clinical Assessments.................................................................47
6.2.5.2. Laboratory Assessments............................................................48
6.2.5.3. Oral Switch Therapy Administration ........................................48
6.2.5.4. Microbiological Assessments....................................................48
6.2.6. End of Treatment (Oral or OPAT): Part B Only ........................................48
6.2.6.1. Laboratory Assessments............................................................49
6.2.6.2. Microbiological Assessments....................................................49
6.2.7. Test of Cure (TOC): Part B Only ...............................................................50
6.2.7.1. Clinical Assessments.................................................................50
6.2.7.2. Laboratory Assessments............................................................50
6.2.7.3. Microbiological Assessments....................................................51
6.2.8. Late Follow-Up (LFU) ...............................................................................51
6.2.8.1. Part A.........................................................................................51
6.2.8.2. Part B.........................................................................................51
6.3. Subject Withdrawal [Early Termination]................................................................52
7. ASSESSMENTS..................................................................................................................53
7.1. Pharmacokinetics ....................................................................................................53
7.1.1. Plasma for Analysis of Ceftazidime - Avibactam ......................................53
7.2. Banked Biospecimens .............................................................................................55
7.2.1. Additional Research....................................................................................55
7.3. Microbiology...........................................................................................................55
7.3.1. Blood Sample for Culture...........................................................................55
7.3.2. Urine Sample for Culture............................................................................56
7.3.3. Other Specimens and Tissue Samples for Culture .....................................56
7.4. Safety Assessments .................................................................................................56
7.4.1. Laboratory Safety Assessments..................................................................56
7.5. Blood Volume .........................................................................................................57


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8. ADVERSE EVENT REPORTING......................................................................................58
8.1. Requirements...........................................................................................................58
8.1.1. Additional Details on Recording Adverse Events on the CRF...................59
8.1.2. Eliciting Adverse Event Information..........................................................59
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal [Early Termination] section)...........................................60
8.1.4. Time Period for Collecting AE/SAE Information......................................60
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................60
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................60
8.1.5. Causality Assessment .................................................................................60
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................61
8.2. Definitions...............................................................................................................61
8.2.1. Adverse Events...........................................................................................61
8.2.2. Abnormal Test Findings .............................................................................62
8.2.3. Serious Adverse Events ..............................................................................62
8.2.4. Hospitalization............................................................................................63
8.3. Severity Assessment................................................................................................64
8.4. Special Situations ....................................................................................................64
8.4.1. Protocol-Specified Serious Adverse Events...............................................64
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................64
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................66
8.4.3.1. Exposure During Pregnancy......................................................66
8.4.3.2. Exposure During Breastfeeding ................................................66
8.4.3.3. Occupational Exposure .............................................................66
8.4.4. Medication Errors and Lack of Efficacy ....................................................67
8.4.4.1. Medication Errors......................................................................67
8.4.4.2. Lack of Efficacy........................................................................67
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................68
9.1. Sample Size Determination.....................................................................................68
9.2. Pharmacokinetic Analysis (Primary Objective Part A, Secondary Objective 
Part B)........................................................................................................................69
9.3. Safety Analysis (Primary Objective Part B, Secondary Objective Part A).............69


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9.4. Efficacy Analysis (Secondary Objective Part B) ....................................................70
9.4.1. Efficacy Response Definitions ...................................................................71
9.4.2. Microbiological Response Definitions .......................................................72
9.5. Interim Analysis ......................................................................................................73
9.6. Data Monitoring Committee ...................................................................................73
9.7. Safety Review Committee.......................................................................................73
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................74
11. DATA HANDLING AND RECORD KEEPING .............................................................74
11.1. Case Report Forms/Electronic Data Record .........................................................74
11.2. Record Retention...................................................................................................75
12. ETHICS..............................................................................................................................75
12.1. Institutional Review Board/Ethics Committee......................................................75
12.2. Ethical Conduct of the Study ................................................................................76
12.3. Subject Information and Consent..........................................................................76
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................77
13. DEFINITION OF END OF TRIAL...................................................................................77
13.1. End of Trial in a Member State.............................................................................77
13.2. End of Trial in All Other Participating Countries.................................................77
14. SPONSOR DISCONTINUATION CRITERIA ................................................................78
15. PUBLICATION OF STUDY RESULTS..........................................................................78
15.1. Communication of Results by Pfizer ....................................................................78
15.2. Publications by Investigators ................................................................................79
16. REFERENCES ..................................................................................................................81
LIST OF TABLES
Table 1.
Identity of Investigational Product .......................................................................34
Table 2.
CAZ-AVI Weight-based Doses for Each Cohort .................................................35
Table 3.
Laboratory Safety Variables.................................................................................57
Table 4.
Volume of Blood to be Drawn from Each Subject...............................................58
Table 5.
Definition of Clinical Response Categories at the EOIV, EOT, TOC and 
LFU.......................................................................................................................71
Table 6.
Per-Pathogen Microbiological Outcomes Categories at TOC..............................72


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Table 7.
Per-Subject Microbiological Response.................................................................72
Table 8.
Emergent Infections..............................................................................................73
LIST OF FIGURES
Figure 1.
Study Outline........................................................................................................26
Figure 2.
Cohort Start Up.....................................................................................................27
Figure 3.
Pharmacokinetic CAZ-AVI Sample Collection Time Points...............................54
Figure 4.
Study Analysis Sets ..............................................................................................68
APPENDICES
Appendix 1. Abbreviations......................................................................................................82
Appendix 2. Calculation of Corrected Age for Pre-Term Infant Eligibility for Cohort 1.......85
Appendix 3. Table of Potential Alternative Doses of CAZ-AVI for Infants and 
Neonates ...............................................................................................................86


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PROTOCOL SUMMARY
Background and Rationale
Ceftazidime is an injectable third generation cephalosporin antibiotic which has been in 
clinical use worldwide for more than 25 years for the treatment of infections caused by 
aerobic Gram-negative pathogens.  Ceftazidime has been shown to be safe and effective in 
adult and pediatric patients (neonates to adolescents <18 years of age) for a range of 
indications.  However, over the past 15 years, resistance to ceftazidime has been increasing 
worldwide.  The most common mechanism of resistance is bacterial production of 
-lactamases, in particular, extended spectrum -lactamases (ESBLs).
In order to counter ceftazidime resistance and restore antibacterial activity to ceftazidime, a 
combination product has been developed in which ceftazidime is combined with avibactam, a 
novel non--lactam -lactamase inhibitor.  Although avibactam itself possesses no intrinsic 
antibacterial activity, it has been shown to restore activity of ceftazidime against clinically 
relevant -lactamases of Class A and Class C varieties, including extended spectrum 
-lactamases (ESBLs) and serine-based Klebsiella pneumoniae carbapenemases (KPCs) and 
AmpC producing strains.  Although avibactam has no inhibitory effect on Class B 
metallo--lactamases, it does inhibit the activity of some Class D -lactamases
(eg, OXA-48 type carbapenemase).  A fixed dose combination of ceftazidime and avibactam 
(CAZ-AVI) was approved for use in adults in the United States in 2015, and for use in 
children three months of age and older in 2019 for complicated intra-abdominal infection
(cIAI) (in combination with metronidazole) and complicated urinary tract infection (cUTI),
under the brand name AVYCAZ.1 A fixed dose combination of ceftazidime and avibactam 
(CAZ-AVI) was approved for use in adults in Europe in 2016 under the brand name 
Zavicefta.2  This fixed-dose combination of CAZ-AVI is currently being evaluated globally 
for pediatric use in hospital-acquired pneumonia/ventilator associated pneumonia
(HAP/VAP).
Study Sites and Number of Subjects Planned
This study is planned to be performed at approximately 40 sites and 15 countries in the 
United States (US), Europe, and Asia.
The study will be conducted in 2 parts, Part A and Part B.  Part A is a non-randomized 
open-label single-dose pharmacokinetic (PK) study enrolling at least 24 neonates and infants 
from 26 weeks gestational age (GA) to <3 months of age who are hospitalized and receiving 
other intravenous antibiotics for suspected or confirmed bacterial infection.  Part B is a 
non-randomized open-label, multi-dose, single treatment arm PK study enrolling at least 
24 neonates and infants from 26 weeks GA to <3 month of age who are hospitalized with 
suspected or confirmed aerobic Gram-negative bacterial infections (excluding central 
nervous system infections) requiring intravenous antibiotic therapy.


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Parts A and B will each be divided into 3 age cohorts:
Cohort
Age
Part A
Part B
1
Term infants (GA 37 weeks) age >28 days to <3 months (<89 days) or 
pre-term infants with corrected age >28 days to <3 months (<89 days)*
n=8
n=8
2
Term neonates (GA 37 weeks) from birth to 28 days
n=8
n=8
3
Pre-term neonates (GA 26 to <37 weeks) from birth to 28 days
n=8
n=8
*The number of pre-term corrected age infants in Cohort 1 is limited to 3 each in Parts A and B.  Sites will be 
notified in writing if this limit is reached.
GA = Gestational Age, the time elapsed between the first day of the last menstrual period and birth.
Corrected age is the age of the infant from the expected date of delivery, calculated by subtracting the number 
of weeks born before 40 weeks of gestation from the chronological age (Engle, 2004).3  Corrected age (weeks)
= chronological age in weeks – (40 – gestational age in weeks).  See Appendix 2 for calculation of corrected 
age in days and alternative perinatal age terminologies.
Enrollment for this study will begin with Cohort 1 of Part A.  A Safety Review Committee 
(SRC) consisting of the study team physician, international coordinating Investigator or 
delegate, global safety/risk lead or delegate, therapeutic area director or delegate and the 
clinical pharmacologist/pharmacometrician or delegates will assess the PK, safety and 
toleration of CAZ-AVI in the first 4 subjects in Cohort 1 of Part A prior to initiating 
simultaneous enrollment of the remaining cohorts in Part A and Cohorts 1 and 2 in Part B.  
Based on this assessment the SRC in conjunction with the external data monitoring 
committee (E-DMC) may recommend a dose adjustment from Appendix 3 and/or a modified 
enrollment sequence which will be communicated to the study sites in a written protocol 
Clarification Memorandum and incorporated into the next protocol version.  A similar 
assessment will be conducted after the first 4 subjects are enrolled into each cohort of Part A 
and Part B. Enrollment will not begin in Cohort 3 of Part B until the SRC has conducted its 
review of the first 4 subjects in Cohort 3 of Part A. If CAZ-AVI safety, toleration or PK are 
not consistent with expectations after the first 4 subjects in any Cohort then it may be 
necessary to delay or stagger the remaining cohorts to gain more experience, in which case 
an updated Pfizer and EDMC approved cohort enrollment sequence will be provided to sites 
in a written protocol Clarification Memorandum.
Objectives and Endpoints
Part A Primary Objective:
Part A Primary Endpoints:
To characterize the pharmacokinetics of a single 
intravenous dose of ceftazidime-avibactam in 
hospitalized neonates and infants from birth to 
<3 months.
CAZ and AVI plasma concentrations by nominal 
sampling time.
Part A Secondary Objective:
Part A Secondary Endpoint:
To evaluate the safety and tolerability of a single 
intravenous dose of ceftazidime-avibactam in 
hospitalized neonates and infants from birth to 
<3 months.
Safety and tolerability endpoints include adverse events, 
serious adverse events, deaths, discontinuations due to 
adverse events and laboratory abnormalities.


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Part B Primary Objective:
Part B Primary Endpoint:
To evaluate the safety and tolerability of 
ceftazidime-avibactam for the treatment of 
aerobic Gram-negative infection in neonates and 
infants from birth to <3 months.
Safety and tolerability endpoints include adverse events, 
serious adverse events, deaths, discontinuations due to 
adverse events and laboratory abnormalities.
Part B Secondary Objectives:
Part B Secondary Endpoints:
To evaluate the pharmacokinetic profile of 
multiple intravenous doses of 
ceftazidime-avibactam in hospitalized neonates 
and infants from birth to <3 months.
CAZ and AVI plasma concentrations by nominal 
sampling time.
To evaluate the efficacy of 
ceftazidime-avibactam for the treatment of 
aerobic Gram-negative infection in neonates and 
infants from birth to <3 months.
Efficacy outcome measures will include:

All-cause mortality.

Clinical outcome at End-of-Intravenous, 
End-of-Treatment, Test-of-Cure and Late 
Follow-Up.

Cure defined as clinical improvement and no need 
for further antibiotic treatment, 7 to 14 days after end 
of treatment.

Microbiological eradication 7 to 14 days after end of 
treatment (micro-Intent-to-Treat analysis set).

Emergent infections.
Study Design
This is a 2-part Phase 2a, non-randomized, multicenter, open-label, single and multi-dose PK 
study to assess PK, safety, and tolerability of CAZ-AVI in neonates and young infants aged 
birth to <3 months.  The efficacy of CAZ-AVI for the treatment of aerobic Gram-negative 
infection will be assessed as a secondary objective in the multi-dose portion of the trial.
In Part A subjects will have a Screening visit (Visit 1), a Baseline visit (Visit 2) during which 
they will receive a single intravenous (IV) infusion of CAZ-AVI followed by timed PK 
assessments, and then 2 follow-up assessments at 24 and 48 hours after the start of the 
infusion, and a Late Follow-up assessment 28-35 days after the infusion.  In Part B, subjects 
will have a Screening visit (Visit 1), a Baseline visit (Visit 2) during which they will start 
IV treatment with CAZ-AVI, and then ongoing treatment for 2-14 days (with an optional 
switch to alternative oral therapy or outpatient parenteral antimicrobial therapy (OPAT) with 
another IV antibiotic after at least 48 hours of IV CAZ-AVI, an End-of-Intravenous (EOIV) 
Treatment assessment within 24 hours after the last IV infusion of CAZ-AVI, and 
End-of-Treatment (EOT) assessment within 48 hours after the last oral or OPAT treatment (if 
applicable), a Test-of-Cure (TOC) assessment 7-14 days after the last dose of any drug (IV or 
oral) and a Late Follow-Up (LFU) assessment 28-35 days after the last IV infusion of 
CAZ-AVI.


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For Part A and Part B, three single PK blood samples, each 0.3 mL, (2 x 0.3 mL for 
premature infants weighing less than 1 kg) will be obtained during the 6 hours following the 
infusion.  For Part A, PK samples will be collected after a single dose of CAZ-AVI has been 
infused.  For Part B, the PK samples will be collected after at least 3 consecutive doses of 
CAZ-AVI have been infused.
Each subject is expected to complete the study, including the Late Follow-Up visit.  
Participants in the study must be inpatients at the study site institution to receive study 
medication, however an optional switch to alternative oral therapy or OPAT after at least
48 hours of CAZ-AVI is permitted in Part B with subsequent hospital discharge if 
appropriate.  Subjects who are not evaluable for PK will be replaced.  An evaluable subject is 
one who has received a single IV dose of CAZ-AVI in Part A or at least 3 consecutive doses
of CAZ-AVI in Part B and has at least 1 ceftazidime and/or avibactam plasma measurement 
available.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The Investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Part A Schedule of Activities
Protocol Activity
Screeninga
Baseline/
IV Infusion
24 hr
Assessment
48 hr
Assessment
Late Follow-Up
(LFU)b
Visit Number
Visit 1
Visit 2 
Visit 3
Visit 4
Visit 5
Study Day
Days -1 to 1
Day 1
Day 2
Day 3
Day 28-35
Clinic Assessments
Informed consent
X
Inclusion/Exclusion criteria
X
Demography
X
Medical history (including pre- and post-birth)
X
Physical examination
X
X
X
X
Length
X
Weight (first weight of the day)
X
X
X
X
Vital signs evaluationc
Xd
X
X
X
Oxygen saturation (if available)
X
X
X
X
Serious and Non-Serious Adverse event assessment
X
X
X
X
X
Adjunctive therapeutic procedures (if any)
X
X
X
CXR, CT scan, or other imaging tests
Xe
Xf
Laboratory Assessmentsg
Hematologyh
X
Xf
X
Xf
Blood chemistryh
X
Xf
X
Xf
Urinalysish
X
Xf
X
Xf
Urine outputi
X
X
X
Study Medication
CAZ-AVI Infusion
X
Pharmacokinetic (PK) blood samplingj
X


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Protocol Activity
Screeninga
Baseline/
IV Infusion
24 hr
Assessment
48 hr
Assessment
Late Follow-Up
(LFU)b
Visit Number
Visit 1
Visit 2 
Visit 3
Visit 4
Visit 5
Study Day
Days -1 to 1
Day 1
Day 2
Day 3
Day 28-35
Concomitant Treatmentk
X
X
X
X
Abbreviations: CAZ-AVI = ceftazidime-avibactam; CT scan = computed tomography scan; CXR = chest x-ray; PK = Pharmacokinetic.
a.
Screening assessments can serve as baseline if they are completed on the same calendar day as Day 1, prior to CAZ-AVI infusion, but they must be 
completed no earlier than the day before the start of CAZ-AVI infusion (except for laboratory assessments which may be up to 2 days before the start of 
CAZ-AVI infusion, as noted in footnote g).  If additional assessments are conducted per standard of care prior to the first infusion of CAZ-AVI the 
assessments closest to the infusion will be considered baseline.
b.
The Late Follow-up (LFU) visit to capture any potential adverse events or serious adverse may be conducted by telephone.
c.
Vital signs (blood pressure, heart rate/pulse, respiratory rate and temperature).  Post-baseline, record the daily highest and lowest temperature measurements.  
Additional vitals may be taken as needed.
d.
Record at least 2 heart rate/pulse measurements taken during a 30 minute period.  Record at least 2 blood pressure measurements, or record highest and 
lowest measurements if continuously monitored, over a 30 minute period.
e.
At screening, obtain results of CXR, CT scan, or other imaging tests (eg, echocardiogram, CT scan, magnetic resonance imaging (MRI), ultrasound) if 
performed as part of the subject’s regular medical care up to 3 days before screening.
f.
If clinically indicated and performed as part of subject's regular medical care.
g.
If the subject is improving and laboratory assessments were performed within 2 days of CAZ-AVI infusion, those test results may be used for eligibility and 
they do not need to be repeated for screening.
h.
Refer to Section 7.4.1 for list of tests.
i.
For subjects who have been hospitalized for 8 hours, calculate urine output over the last 8 hour period.
j.
Blood samples for PK (0.3 mL per sample) will be collected on Day 1 following IV infusion of CAZ-AVI, at the following time points: 1) anytime within 
15 minutes after stopping CAZ-AVI infusion, 2) anytime between 30 minutes and 90 minutes after stopping CAZ-AVI infusion, and 3) anytime between 
300 minutes (5 hours) and 360 minutes (6 hours) after stopping CAZ-AVI infusion.  If the dosing interval for any cohort is increased from every 8 hour to 
every 12 hours, then timing of the third PK sample will be changed to anytime between 540 minutes (9 hours) and 600 minutes (10 hours) after stopping 
CAZ-AVI infusion.  Preference should be given to the first and third collection time if only two PK samples are obtained for any reason.  For infants 
weighing less than 1 kg only the first and third PK blood sample will be collected.  PK blood samples are NOT to be drawn if the subject received a blood or 
blood component transfusion within the past 24 hours.  For subjects who are at risk from additional blood loss, collection of PK samples will require 
assessment by the Investigator.
k.
Review and record prior and concomitant medications taken or received within 7 days before the first dose of study therapy, including, but not limited to, all 
antimicrobials, parenteral nutrition, and blood and blood component transfusions.  For subjects who are being breast fed, record all medications taken by the 
lactating mother for 3 days before the CAZ-AVI infusion through Day 3.


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Part B Schedule of Activities
Protocol Activity
Screeninga
Baseline/1st
IV Infusion
Treatment
End of IV
Treatmentb
End of
Treatmentc
Test of
Cured
Late
Follow-Upe
Visit Number
Visit 1
Visit 2
Visits
3 to 15
Visit 16
Visit 17
Visit 18
Visit 19
Study Daya
Days -1 to 1
Day 1
Days
2 to 14
24 hr after
last IV
infusion
48 hr after
last drug
dose
7-14 Days
after last
drug dose
28-35 days
after last 
CAZ-AVI
infusion
Clinic Assessments
Informed consent
X
Inclusion/Exclusion criteria
X
Demography
X
Medical history (including pre- and 
post-birth)
X
Microbiological/Infectious historyf
X
Physical examination
X
X
X
X
X
X
X
Length
X
Weight (first weight of the day)
X
X
X
X
X
X
X
Vital signs evaluationg
Xh
X
X
X
X
X
X
Oxygen saturation (if available)
X
X
X
X
X
X
X
Serious and Non-Serious Adverse event 
assessment
X
X
X
X
X
X
X
Clinical outcome
X
X
X
X
Adjunctive therapeutic procedures (if any)
X
X
X
X
X
X
CXR, CT scan, or other imaging tests
Xi
Xj
Laboratory assessments
Hematologyk
X
Xj
X
Xj
Xj
Blood chemistryk
X
Xj
X
Xj
Xj
Base excess
Xj
CRP and Procalcitonink
Xj
Urinalysisk
X
Xj
X
Xj
Xj
Urine output
Xl
X
X
X
Xj
Study Medication
CAZ-AVI Infusion
X
Xm


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Protocol Activity
Screeninga
Baseline/1st
IV Infusion
Treatment
End of IV
Treatmentb
End of
Treatmentc
Test of
Cured
Late
Follow-Upe
Visit Number
Visit 1
Visit 2
Visits
3 to 15
Visit 16
Visit 17
Visit 18
Visit 19
Study Daya
Days -1 to 1
Day 1
Days
2 to 14
24 hr after
last IV
infusion
48 hr after
last drug
dose
7-14 Days
after last
drug dose
28-35 days
after last 
CAZ-AVI
infusion
Pharmacokinetic (PK) blood samplingn
X
Concomitant Treatmento
X
X
X
X
X
X
X
Microbiologyp
Blood Culture
Xj
Urine Culture
Xj
Other specimen or tissue culture
Xj
Abbreviations: CAZ-AVI = ceftazidime-avibactam; CRP = C-Reactive Protein; CT scan = computed tomography scan; CXR = chest x-ray; IV = Intravenous.
a.
Screening assessments can serve as baseline if they are completed on the same calendar day as Day 1, prior to CAZ-AVI infusion, but they must be 
completed no earlier than the day before the start of CAZ-AVI infusion.  If additional assessments are conducted per standard of care prior to the first 
infusion of CAZ-AVI the assessments closest to the infusion will be considered baseline.
b.
Perform End of IV Treatment (EOIV) assessments within 24 hours after completion of the last infusion of CAZ-AVI or at time of premature discontinuation 
of CAZ-AVI or early withdrawal from the study.  A switch to oral antibacterial therapy or outpatient parenteral antimicrobial therapy (OPAT) may be 
performed at Investigator discretion after at least 48 hours of IV CAZ-AVI therapy.  EOIV assessments must occur before starting oral or OPAT switch 
therapy.  If subjects are discharged from the hospital after a switch to oral therapy or OPAT any remaining study visits may be conducted as outpatients.
c.
Perform End of Treatment (EOT) assessments within 48 hours after the last dose of IV or oral antibacterial therapy, whichever comes later or at time of 
premature discontinuation of antibacterial therapy or early withdrawal from study.  If there is no switch to oral antibacterial therapy or OPAT then EOIV is 
also EOT.  If a subject was previously assessed as a clinical failure, only the safety assessments need to be performed (ie, AEs and SAEs, concomitant 
medications, adjunctive therapeutic procedures, weight, vital signs, CBC with differential and chemistry panel if clinically indicated and performed as part of 
subject's regular medical care).
d.
Conduct Test of Cure (TOC) assessments 7 to 14 days after the last dose of antibacterial therapy (IV or oral).  If a subject was previously assessed as a 
clinical failure, only the safety assessments need to be performed (ie, AEs and SAEs, concomitant medications, adjunctive therapeutic procedures, weight, 
vital signs, CBC with differential and chemistry panel if clinically indicated and performed as part of subject's regular medical care).


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e.
Conduct Late Follow-up (LFU) assessments, preferably in person 28 to 35 days after the last IV infusion of CAZ-AVI.  The clinical outcome assessed at this 
visit is for relapse or potential re-infection.  The LFU may be conducted via telephone for any subject who has not experienced clinical relapse, did not have 
ongoing AEs or SAEs at TOC, or did not develop AEs or SAEs since TOC.  If symptoms of relapse or new AEs or SAEs are noted, or at the discretion of 
the Investigator, the subject should be immediately scheduled for an in-person visit.  If the visit is in-person, weight, vital signs and oxygen saturation should 
be recorded.  If a subject was previously assessed as a clinical failure, only the safety assessments need to be performed (ie, AEs and SAEs, concomitant 
medications, adjunctive therapeutic procedures, weight, vital signs, CBC with differential and chemistry panel if clinically indicated and performed as part of 
subject's regular medical care).
f.
Obtain any prior microbiological and clinical data (eg, notes in medical records confirming worsening of signs and symptoms of infection) that may help 
determine eligibility.
g.
Vital signs (blood pressure, heart rate/pulse, respiratory rate and temperature).  Post-baseline, record the daily highest and lowest temperature measurements.  
Additional vitals may be taken as needed.
h.
Record at least 2 heart rate/pulse measurements taken during a 30 minute period.  Record at least 2 blood pressure measurements, or record highest and 
lowest measurements if continuously monitored, over a 30 minute period.
i.
At screening, obtain results of CXR, CT scan, or other imaging tests (eg, echocardiogram, CT scan, MRI, ultrasound) if performed as part of the subject’s 
regular medical care up to 3 days before screening.
j.
If clinically indicated and performed as part of subject’s regular medical care.
k.
Refer to Section 7.4.1 for list of tests.  Recommended to repeat at least every 7 days.  If immature neutrophils are available, calculate I/T neutrophil ratio 
using the formula: I/T ratio=Immature cells/Total (mature+immature).
l.
For subjects who have been hospitalized for 8 hours, calculate urine output over the last 8 hour period.
m. Study treatment may be temporarily withheld at the discretion of the Investigator.  See Section 5.5.2.  Optional IV antibiotic coverage for Gram-positive 
organisms, multi-drug resistant Gram-negative organisms, or IV metronidazole for anaerobes may be added per Investigator discretions.  See Section 6.2.1.1, 
Points 2-4.
n.
Blood samples for PK (0.3 mL per sample) will be collected following IV infusion of CAZ-AVI (after at least 3 consecutive doses have been administered), 
at the following time points: 1) anytime within 15 minutes after stopping CAZ-AVI infusion, 2) anytime between 30 minutes and 90 minutes after stopping 
CAZ-AVI infusion, and 3) anytime between 300 minutes (5 hours) and 360 minutes (6 hours) after stopping CAZ-AVI infusion.  If the dosing interval for 
any cohort is increased from every 8 hour to every 12 hours, then timing of the third PK sample will be changed to anytime between 540 minutes (9 hours) 
and 600 minutes (10 hours) after stopping CAZ-AVI infusion.  Preference should be given to the first and third collection time if only two PK samples are 
obtained for any reason.  For infants weighing less than 1 kg only the first and third PK blood sample will be collected.  PK blood samples are NOT to be 
drawn if the subject received a blood or blood component transfusion within the past 24 hours.  For subjects who are at risk from additional blood loss, 
collection of PK samples will require assessment by the Investigator.
o.
Review and record prior and concomitant medications taken or received within 7 days before the first dose of study therapy, including, but not limited to, all 
antimicrobials, parenteral nutrition, and blood and blood component transfusions.  For subjects who are being breast fed, record all medications taken by the 
lactating mother for 3 days before first dose of study therapy through Late Follow-Up (LFU).
p.
Baseline cultures obtained per standard of care should preferably be obtained before any antibacterials are administered.  Cultures should be repeated per 
standard of care upon knowledge of a positive result until sterilization is confirmed.


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Ceftazidime is a bactericidal third generation cephalosporin antibiotic with activity against 
clinically important Gram-negative Enterobacteriaceae and Pseudomonas aeruginosa.  
Ceftazidime is approved for the treatment of aerobic Gram-negative bacterial infections in 
adults and children including neonates (from birth).  Many years of experience using 
ceftazidime have accrued in numerous countries worldwide and its tolerability profile is well 
characterized.  Included among the infections treated by ceftazidime are complicated urinary 
tract infection (cUTI) caused by Pseudomonas aeruginosa, Enterobacter species (spp.), 
Proteus spp., Klebsiella spp., and Escherichia coli (E. coli); complicated intra-abdominal 
infection (cIAI), including peritonitis, caused by E. coli, Klebsiella spp., Staphylococcus 
aureus (methicillin-susceptible strains); and lower respiratory tract infections caused by 
P. aeruginosa, Klebsiella spp. E. coli, Enterobacter spp., and S. aureus
(methicillin-susceptible strains).  Ceftazidime is also approved for use in a wide range of 
other infections, including but not limited to complicated skin and soft tissue infections 
(cSSTI), bone and joint infections, bronchopulmonary infections in cystic fibrosis, and 
bacteremias (Fortum Summary of Product Characteristics [SmPC] 2016;4 FORTAZ United 
States Package Insert [USPI] 2014).5  Like other -lactam antibiotics, ceftazidime is 
susceptible to hydrolysis by -lactamases thereby rendering it inactive.  The high and 
increasing prevalence of -lactam resistance has reduced the utility of ceftazidime in many 
countries.
Avibactam is a novel, non--lactam, -lactamase inhibitor.  Beta-lactamase inhibition by 
avibactam is effected through the formation of a stable covalent carbamoyl linkage to the 
enzyme complex.  Although avibactam itself possesses no intrinsic antibacterial activity, it 
has been shown to restore in vitro activity of ceftazidime against Class A, Class C and some 
Class D -lactamase-producing pathogens including those commonly associated with cIAI, 
cUTI, and nosocomial pneumonia (NP).  Avibactam, when combined with ceftazidime, has 
also been shown to be active against strains that express a combination of -lactamase types, 
as well as strains that are concomitantly resistant to other antibacterial classes such as 
fluoroquinolones.  Unlike currently available -lactamase inhibitors, avibactam does not 
induce -lactamase production (Miossec et al., 2013).6
A fixed dose combination of ceftazidime-avibactam (referred to hereafter as CAZ-AVI) was 
approved for use in adults by the FDA on 25 February 2015 and in children three months of 
age and older on 14 Mar 2019 for cIAI (in combination with metronidazole) and cUTI, and it 
is marketed under the tradename AVYCAZ.1  On 24 June 2016, the European Commission 
granted European Union marketing authorization for the use of CAZ-AVI in adults under the 
tradename Zavicefta.2  CAZ-AVI has received regulatory approval in 51 countries 
worldwide.
The fixed dose combination ceftazidime-avibactam is currently being evaluated globally for 
pediatric use in HAP/VAP.


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CAZ-AVI is indicated in the US and Europe for the treatment of adults with complicated 
intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), and 
hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP).  It is 
also indicated in Europe for the treatment of infections due to aerobic Gram-negative 
organisms in adult patients with limited treatment options.  CAZ-AVI is indicated in the US 
for the treatment of children three months of age and older with cIAI (in combination with 
metronidazole) and for children with cUTI.
1.2. Background
CAZ-AVI is currently being evaluated for use in pediatric patients.  PK in pediatric subjects 
aged 3 months to 18 years was investigated in Study D4280C00014, a Phase 1, multicenter, 
open-label study.  In that study pediatric subjects receiving other systemic antibiotic therapy 
for suspected or confirmed infection were administered a single IV infusion of CAZ-AVI 
over 120 minutes.  A total of 35 subjects were enrolled in the study and 32 received the full 
infusion treatment, 8 in each of the 4 age cohorts: 1) aged 12 to <18 years; 2) aged 6 to 
<12 years; 3) aged 2 to <6 years; and 4) age 3 months to <2 years.
A population PK model (CAZ-MS-PED-01) for CAZ-AVI in pediatrics was developed using 
adult PK data and PK data from pediatric subjects in Study D4280C00014.  Based on this 
model, dose regimens were selected for two recently completed Phase 2 pediatric studies, 
D4280C00015/C3591004 and D4280C00016/C3591005, to assess the safety, tolerability and 
descriptive efficacy of CAZ-AVI in children age 3 months to less than 18 years with cIAI 
and cUTI, respectively.
1.3. Rationale for Conducting This Study
The long-established efficacy and safety of ceftazidime in children including neonates (from 
birth), the mode of action of avibactam, and the available Phase 2 clinical data for CAZ-AVI 
in pediatrics provide a strong rationale for extending the evaluation of CAZ-AVI into the 
infant and neonatal population.  CAZ-AVI is expected to provide positive clinical outcomes 
in those pediatrics patients infected with pathogens resistant to -lactam antibiotics due to the 
presence of avibactam sensitive -lactamases.  CAZ-AVI has the potential to address the 
significant unmet clinical need associated with antibiotic resistance in pediatric patients 
including infants/neonates.
The current study will extend the evaluation of CAZ-AVI into infants and premature 
neonates by collecting single and multiple dose pharmacokinetic information, safety, 
tolerability, and descriptive efficacy in newborns less than 3 months of age down to a 
gestational age of 26 weeks.
The inclusion and exclusion criteria have been chosen in order to select appropriate pediatric 
subjects for single dose PK assessment in Part A who are already receiving other 
IV antibiotics for suspected or confirmed bacterial infection.  For the multiple dose PK 
assessment in Part B the enrollment criteria have been chosen to select appropriate pediatric 
subjects who have suspected or confirmed bacterial infection with aerobic Gram-negative 
organisms and sufficient severity to require treatment with IV antibiotics.  Subjects with 


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suspected or confirmed central nervous system (CNS) infection are excluded because 
adequate penetration of CAZ-AVI into the CNS has not been established.  The PK sampling 
and safety assessments are judged to be sufficient to fulfill the primary and secondary 
objectives of the study.
1.4. Dose Rationale
Dosing for this study is based on modelling and simulation study CAZ-MS-PED-02 
(Study 7) which included data from the adult Phase 1, 2, and 3 studies including studies of 
cIAI, cUTI, and NP, and three prior pediatric studies: 1) D4280C00014, an open-label, 
single-dose study in hospitalized pediatric patients from 3 months to <18 years of age 
receiving systemic antibiotic therapy for suspected or confirmed infection; 
2) D4280C00015/C3591004 a Phase 2, single-blind, randomized, multicenter, 
active-controlled, multiple-dose study of CAZ-AVI when given in combination with 
metronidazole and compared with meropenem in hospitalized pediatric patients from 
3 months to <18 years of age with cIAI; and 3) D4280C00016/C3591005 a Phase 2, 
single-blind, randomized, multicenter, active-controlled, multiple-dose study of CAZ-AVI 
compared with cefepime in hospitalized pediatric patients from 3 months to <18 years of age 
with cUTI.
In all population pharmacokinetic (PK) analyses both ceftazidime (CAZ) and avibactam 
(AVI) concentration time courses have been well described by a linear 2-compartment PK
model with first-order elimination.  Simulations based on the final population described 
above were used to provide dose recommendations for all pediatric patients from pre-term 
neonates to <18 years of age with normal renal function, mild, moderate, or severe renal 
impairment.  Per dose regimen and age scenario sets of 1,000 pediatric PK parameters were 
simulated with between-subject variability simulated non-parametrically through resampling 
of individual random effect estimates from the final CAZ and AVI models.  The exposure 
target was defined as achieving at least 50 percent of time during the dosing interval that 
CAZ and AVI are simultaneously above the minimum inhibitory concentration (MIC) of 
8 mg/mL for CAZ and Critical threshold concentration (CT) of 1.0 mg/L for AVI, 
respectively.  The Probability of Target Attainment (PTA) was defined as the percentage of 
simulated patients that simultaneously achieved the exposure targets for both CAZ and AVI. 
The PK/PD targets for CAZ of MIC 8 mg/L and AVI of CT 1.0 mg/L are the same joint 
PK/PD targets used to support approval in adults.
A range of mg/kg doses administered over a 2h infusion were simulated for normal renal 
function.  For simulated infants >28 days to 3 months of age, CAZ-AVI doses of 
30/7.5 mg/kg every 8 hours (q8h) over a 120 minute infusion were predicted to give joint 
PTAs 96% for cUTI, cIAI, and NP and achieve CAZ and AVI maximum plasma 
concentration (Cmax) and area under the plasma concentration-time curve (AUC0-24) 
exposures similar to adult exposures.  Compared with the reference population (adults with 
normal renal function), the CAZ geometric mean Cmax ranged from 93% to 94% and the 
AUC0-24 ranged from 94% to 99%.  The AVI geometric mean Cmax ranged from 95% to 
105% and the AUC0-24 ranged from 96% to 103%.  For simulated full-term neonates, 
CAZ-AVI doses of 20/5 mg/kg q8h were predicted to achieve 96% PTAs for cUTI, cIAI, 


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and NP while maintaining CAZ and AVI Cmax and AUC0-24 exposures slightly lower than 
reference adult exposures.  The CAZ geometric mean Cmax ranged from 72% to 73% and the 
AUC0-24 ranged from 82% to 87% of corresponding adult values.  The AVI geometric mean 
Cmax ranged from 71% to 78% of adult values and the AUC0-24 ranged from 77% to 83%.  
For simulated pre-term neonates, CAZ-AVI doses of 20/5 mg/kg q8h were predicted to 
achieve 99% PTAs for cUTI, cIAI, and NP while maintaining CAZ and AVI Cmax
exposures similar or slightly lower than adults and AUC0-24 exposures slightly higher than 
adults. The CAZ geometric mean Cmax ranged from 95% to 97% of values for the reference 
adult patients while the AUC0-24 ranged from 130% to 138% of corresponding adult values.  
The AVI geometric mean Cmax ranged from 85% to 92% of reference adult values and the 
AUC0-24 ranged from 104% to 112%.
Based on the simulation study CAZ-MS-PED-02 (Study 7), dosing for this study will be 
initiated using an 8 hour dosing interval and 120 minute infusion for all cohorts with 
CAZ-AVI doses of: 30/7.5 mg/kg q8h for infants >28 days to <3 months of age (including 
pre-term infants with corrected age in this interval) and 20/5 mg/kg q8h for full- and pre-term 
infants.  These doses for the ceftazidime component are within the mg/kg/day range for 
approved doses of 100-150 mg/kg/day in 3 divided doses for infants >2 months of age and 
25-60 mg/kg/day in 2 divided doses for neonates and infants 2 months of age in the EU 
(Fortum SmPC, 2016)4 and the approved doses of 30-50 mg/kg q8h in infants >1 month of 
age and 30 mg/kg every 12 hours (q12h) in neonates and infants 0-4 weeks of age in the US 
(FORTAZ USPI, 2014).5  If emerging PK data during the study suggest that the alternative 
dosing interval of 12 hours for term and/or pre-term neonates in Cohort 2 and Cohort 3, 
respectively, would be more appropriate, this information will be provided to Investigators in 
a written protocol Clarification Memorandum from the Sponsor.  Other potential dosing 
regimens are provided in Appendix 3 which may be utilized only upon written notice from 
the Sponsor in a protocol Clarification Memorandum.  Any dosing modifications provided in 
a protocol Clarification Memorandum will be incorporated into the next version of the 
protocol.
1.5. Benefit/Risk and Ethical Assessment
The potential benefit of the study, in general, is the identification of a novel antibiotic 
combination product that is an effective treatment for infections in infants and neonates, in 
the face of the changing pattern of antibiotic resistance.  In Part A, CAZ-AVI will not be 
used to treat the infection for which the subject is receiving IV antibiotics, as Part A is not a 
therapeutic study.  The potential benefit to subjects participating in Part B of this study is that 
they will receive effective antibiotic therapy for their infection.  It is possible that CAZ-AVI 
will not prove to be a sufficiently effective treatment for aerobic Gram-negative organisms in 
Part B, despite the long established efficacy of ceftazidime alone.  This risk is mitigated by 
the allowed option of adding an aminoglycoside antibiotic, by close monitoring of study 
subjects, and by management with appropriate other therapies as determined by the 
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The risk considerations for this study encompass the known and potential risks for the 
development product CAZ-AVI and its component products ceftazidime and avibactam.  
Additionally there may be risks associated with other treatments that may be administered as 
described in this protocol (ampicillin, vancomycin, or optional aminoglycoside).  As the risks 
for these marketed products are widely available in their respective prescribing information, 
these risks are not discussed within this section.
The full risk profile for ceftazidime is described in the prescribing information for the 
product (refer to local ceftazidime product labeling).  Important risks as laid out in the 
warnings and precautions in product labeling for ceftazidime include the following:

Elevated levels of ceftazidime used in patients with renal impairment have been 
associated with neurological sequelae such as tremor, myoclonus, seizures, 
encephalopathy and coma.
The adverse events (AEs) described below for ceftazidime may occur with multiple 
administrations and are unlikely to occur with the single dose that subjects in Part A will be 
receiving:

Antibiotic-associated diarrhea, Clostridium difficile diarrhea, colitis, and 
pseudomembranous colitis;

Bacterial overgrowth with nonsusceptible organisms.
The risks for CAZ-AVI in neonates/infants have not been fully elucidated; however, it is 
assumed that known or potential risks for CAZ-AVI should include those identified in the 
approved local label for CAZ-AVI, eg the US Package Insert (USPI) (AVYCAZ, 2019)1 or 
the EU Summary of Product Characteristics (SmPC) (Zavicefta, 2018).2  Thus far, no unique 
risks have been identified for the combination of ceftazidime and avibactam in 
infants/children. In recently completed study D4280C00015/C3591004, CAZ-AVI plus 
metronidazole was well tolerated for the treatment of pediatric patients 3 months of age to 
<18 years of age with cIAI.  Highly favorable clinical and microbiological response rates 
were observed across all patients in the study and against the predominant cIAI pathogens 
(E. coli and P. aeruginosa), and no new safety concerns were identified.  In recently 
completed study D4280C00016/C3591005, CAZ-AVI was generally well tolerated and 
appeared effective for the treatment of pediatric patients 3 months of age to <18 years of age 
with cUTI, and no new safety concerns were identified.  Side effects identified for the 
avibactam component of CAZ-AVI include injection site redness and injection site bruising.
Additional information for CAZ-AVI may be found in the single reference safety document 
(SRSD), which for this study is the CAZ-AVI Investigator Brochure (IB).


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2. STUDY OBJECTIVES AND ENDPOINTS
Part A Primary Objective:
Part A Primary Endpoints:
To characterize the pharmacokinetics (PK) of a 
single intravenous dose of CAZ-AVI in hospitalized 
neonates and infants from birth to <3 months.
CAZ and AVI plasma concentrations by nominal 
sampling time.
Part A Secondary Objective:
Part A Secondary Endpoint:
To evaluate the safety and tolerability of a single 
intravenous dose of CAZ-AVI in hospitalized 
neonates and infants from birth to <3 months.
Safety and tolerability endpoints include adverse 
events (AEs), serious adverse events (SAEs), deaths, 
discontinuations due to AEs and laboratory 
abnormalities.
Part B Primary Objective:
Part B Primary Endpoint:
To evaluate the safety and tolerability of CAZ-AVI 
for the treatment of aerobic Gram-negative infection 
in neonates and infants from birth to <3 months.
Safety and tolerability endpoints include adverse 
events (AEs), serious adverse events (SAEs), deaths, 
discontinuations due to AEs and laboratory 
abnormalities.
Part B Secondary Objectives:
Part B Secondary Endpoints:
To evaluate the pharmacokinetic profile of multiple 
intravenous doses of CAZ-AVI in hospitalized 
neonates and infants from birth to <3 months.
CAZ and AVI plasma concentrations by nominal 
sampling time.
To evaluate the efficacy of CAZ-AVI for the 
treatment of aerobic Gram-negative infection in 
neonates and infants from birth to <3 months.
Efficacy outcome measures will include:

All-cause mortality.

Clinical outcome at EOIV, EOT, TOC and 
LFU.

Cure defined as clinical improvement and no 
need for further antibacterial treatment, 7 to 
14 days after end of treatment.

Microbiological eradication 7 to 14 days after 
end of treatment (micro-Intent-to-Treat analysis 
set).

Emergent infections.
3. STUDY DESIGN
This is a 2-part Phase 2a non-randomized, multicenter, open-label, single and multi-dose PK 
study to assess PK, safety, and tolerability of CAZ-AVI in neonates and young infants aged 
birth to <3 months.  The efficacy of CAZ-AVI for the treatment of aerobic Gram-negative 
infection will be summarized descriptively as a secondary objective in the multi-dose portion 
of the trial.
The study outline is provided in Figure 1.  The sequence of cohort startup is provided in 
Figure 2.


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Figure 1.
Study Outline
Abbreviations: CAZ-AVI = ceftazidime-avibactam; EOIV = End of IV; EOT = End of Treatment; F/U = Follow-Up; hr(s) = hour(s); ICD = Informed Consent 
Document; IV = Intravenous; LFU = Late Follow-Up; OPAT = outpatient parenteral antimicrobial therapy; TOC = Test of Cure.
Oral or
OPAT
Day -1 to 1
ICD and 
screening the 
day of or day
before 1st dose 
of CAZ-AVI
Day 1
1st Dose of 
CAZ-AVI
Day 2
24 hr F/U
Day 3
48 hr F/U
LFU
28-35
days after 
last dose 
of 
CAZ-AVI
Days 2-14
CAZ-AVI
(min 48hr)
EOIV
EOIV 
and/or
EOT
TOC
Part A
Part B
Optional oral or OPAT 
switch after 48 hrs
IV Days 2-14
IV
Plus optional Gram-positive coverage and 
aminoglycoside as needed


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Figure 2.
Cohort Start Up
Part A Cohort 1: >28 days to <3 months, n=8
Part A Cohort 2: Full Term to 28 days, n=8
Part B Cohort 1: >28 days to <3 months, n=8
Part B Cohort 2: Full Term to 28 days, n=8
Part A Cohort 3: Premature to 28 days, n=8
                           
Part B Cohort 3: Premature to 28 days, n=8
4
4
8
8
8
8
Initiate enrollment with 
Part A Cohort 1
Safety Review Committee (SRC) assesses PK 
and safety after first 4 subjects are completed 
in Part A Cohort 1, before initiating 
simultaneous enrollment of remaining cohorts 
in Part A and Cohorts 1 and 2 in Part B.  SRC 
will also re-assess after the first 4 subjects are 
enrolled into each cohort of Parts A and B. 
*The SRC will assess the PK, safety and 
toleration of CAZ-AVI after the first 
4 subjects are completed in Part A Cohort 3, 
before initiating enrollment in Part B 
Cohort 3.
4*
4


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4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
Subject eligibility should be reviewed and documented by an appropriate member of the 
Investigator’s study team before subjects are included in the study.
The target population for single dose Part A is hospitalized neonates and infants with 
bacterial infection receiving intravenous antibacterial therapy.  The target population for 
multiple dose Part B is hospitalized neonates and infants with suspected or confirmed aerobic 
Gram-negative bacterial infection requiring intravenous antibacterial therapy, excluding 
those with suspected or confirmed CNS infection.
The inclusion and exclusion criteria will be assessed by a site Investigator before enrollment 
of the subject to the study.  Clinically indicated antibacterial treatment must not be delayed 
because a subject is being considered for participation.
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for 
this study.  Under no circumstances can there be exceptions to this rule.  If there is 
uncertainty about whether a specific subject meets inclusion/exclusion criteria this may be 
discussed with the Medical Monitor, but the Medical Monitor cannot waive any of the 
enrollment criteria.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
4.1.1. Inclusion Criteria for All Subjects
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject’s parent(s), legal guardian, or legally acceptable representative has been 
informed of all pertinent aspects of the study. 
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
3. Male or female neonates and infants with age at Screening:
a.
Cohort 1: Full term infants (gestational age 37 weeks) with chronological 
age >28 days to <3 months (<89 days) or pre-term infants with corrected age*
>28 days to <3 months (<89 days).  A maximum of 3 pre-term corrected age 
infants may be enrolled in each part (A and B) of Cohort 1.  Sites will be notified 
in writing if this limit is reached.


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b. Cohort 2: Full term neonates (gestational age 37 weeks) from birth to 28 days.
c.
Cohort 3: Pre-term neonates (gestational age 26 to <37 weeks) from birth to 
28 days.
Gestational age is the time elapsed between the first day of the last menstrual period 
and birth
*Corrected age is the age of the infant from the expected date of delivery, calculated 
by subtracting the number of weeks born before 40 weeks of gestation from the 
chronological age (Engle, 2004).3 Corrected age (in weeks) = chronological age in 
weeks – (40 – gestational age in weeks).  See Appendix 2 for calculation of corrected 
age in days and alternative perinatal age terminologies.
4.1.2. Inclusion Criteria for Part A Subjects Only
1. Hospitalized and receiving intravenous antibacterial therapy for the treatment of a 
suspected or confirmed bacterial infection.
4.1.3. Inclusion Criteria for Part B Subjects Only
1. Hospitalized with suspected or confirmed aerobic Gram-negative bacterial infection 
requiring intravenous antibacterial therapy.
2. Subjects must meet at least 1 clinical and 1 laboratory criterion or meet at least 2 of 
the clinical criteria:
Clinical Criteria:
a.
Hypothermia (<36C) OR fever (>38.5C);
b. Bradycardia OR tachycardia OR rhythm instability;
c.
Urine output 0.5 to 1 mL/kg/h OR hypotension OR mottled skin OR impaired 
peripheral perfusion;
d. Petechial rash OR sclerema neonatorum;
e.
New onset or worsening of apnea episodes OR tachypnea episodes OR 
increased oxygen requirements OR requirement for ventilation support;
f.
Feeding intolerance OR poor suckling OR abdominal distension;
g. Irritability;
h. Lethargy;
i.
Hypotonia.


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Laboratory Criteria:
a.
White blood cell count 4.0 × 109/L OR 20.0 × 109/L;
b. Immature to total neutrophil ratio >0.2;
c.
Platelet count 100 × 109/L;
d. C-reactive protein (CRP) >15 mg/L OR procalcitonin 2 ng/mL;
e.
Hyperglycemia OR Hypoglycemia;
f.
Metabolic acidosis.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
4.2.1. Exclusion Criteria for All Subjects
1. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the Investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
2. Participation in another clinical study involving investigational drug(s) within 30 days 
prior to study entry and/or during this study participation or have previously 
participated in the current study or in another study of CAZ-AVI (in which an active 
agent was received).
3. Use of potent inhibitors of organic anion transporters OAT1 and/or OAT3 
(eg, probenecid, p-aminohippuric acid (PAH), or teriflunomide) are prohibited.  This 
prohibition of OAT1 and/or OAT3 inhibitors also applies to the mothers of any 
neonates or infants who are breast feeding during the trial.
4. Other acute or chronic medical or laboratory abnormality that may increase the risk 
associated with study participation or investigational product administration or may 
interfere with the interpretation of study results and, in the judgment of the 
Investigator, would make the subject inappropriate for entry into this study.
5. Documented history of any hypersensitivity or allergic reaction to any -lactam 
antibiotic.
6. Refractory septic shock within 24 hours before screening that does not resolve after 
60 minutes of vasopressor therapy.


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7. Moderate or severe renal impairment defined as serum creatinine 2 times the upper 
limit of normal (ULN) for age OR urine output <0.5 mL/kg/h (measured over at least 
8 hours) OR requirement for dialysis.  Deterioration of renal function after enrollment 
during Part B of the study will be handled on a case-by-case basis in discussion with 
the Medical Monitor (see Section 5.5.2).
8. Evidence of progressively fatal underlying disease, or life expectancy of 60 days.
9. Documented history of seizure.
10. Active acute viral hepatitis or acute hepatic failure.
11. Known Clostridium difficile associated diarrhea.
12. Requiring or currently taking antiretroviral therapy for human immunodeficiency 
virus (HIV) or known HIV positive mother.
13. Any condition (eg, cystic fibrosis, urea cycle disorders), antepartum/peripartum 
factors, or procedures that would, in the opinion of the Investigator, make the subject 
unsuitable for the study, place a subject at risk, or compromise the quality of data.
14. Treatment with ceftazidime within 12 hours of CAZ-AVI administration.
4.2.2. Exclusion Criteria for Part A Subjects Only
1. Subject received a blood or a blood component transfusion within 24 hours of the 
start of CAZ-AVI infusion.
2. Subject is expected to be discharged less than 24 hours after the start of CAZ-AVI 
infusion.
4.2.3. Exclusion Criteria for Part B Subjects Only
1. At study entry, subject has confirmed or strongly suspected infection with a pathogen 
known to be resistant to CAZ-AVI or only a Gram-positive pathogen or viral, fungal, 
or parasitic pathogens as the sole cause of infection.
2. Confirmed or suspected central nervous system (CNS) infection (eg, meningitis, brain 
abscess, subdural abscess).
3. Anticipated need for antibacterial therapy longer than 14 days (eg, osteomyelitis, 
endocarditis).  This applies to both study treatment with CAZ-AVI as well as 
adjunctive IV antibacterial treatment for suspected co-infection with Gram-positive 
organisms or multi-drug resistant Gram-negative organisms.
4. Receipt of more than 24 hours of nonstudy systemic antibacterial treatment for 
Gram-negative organisms after culture and before administration of study doses of 
CAZ-AVI.  Empiric coverage with an aminoglycoside for suspected multidrug 
resistant organisms is permitted, provided CAZ-AVI is initiated within 24 hours after 
culture.


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5. Intravenous treatment with chloramphenicol within 24 hours of administration of 
study doses of CAZ-AVI.
6. Subject is expected to be discharged less than 48 hours after the start of CAZ-AVI 
infusion.
4.3. Randomization Criteria
This study is not randomized.  All enrolled subjects will receive CAZ-AVI either as a single 
dose in Part A or multiple doses in Part B.
4.4. Cohort Enrollment Sequence
Enrollment for this study will begin with Cohort 1 of Part A.  A Safety Review Committee 
(SRC) consisting of the study team physician, international coordinating Investigator or 
delegate, global safety/risk lead or delegate, therapeutic area director or delegate and the 
clinical pharmacologist/pharmacometrician or delegates will assess the PK, safety and 
toleration of CAZ-AVI in the first 4 subjects in Cohort 1 of Part A prior to initiating 
simultaneous enrollment of the remaining cohorts in Part A and Cohorts 1 and 2 in Part B.  If 
CAZ-AVI concentrations or safety/toleration are not as expected in the first 4 subjects in 
Cohort 1 of Part A, then the SRC in conjunction with the EDMC may recommend a dose 
adjustment from Appendix 3 and/or a modified enrollment sequence which will be 
communicated to the study sites in a written protocol Clarification Memorandum and 
incorporated into the next protocol version.  A similar assessment will be conducted after the 
first 4 subjects are enrolled into each cohort of Part A and Part B.  Enrollment will not begin 
in Cohort 3 of Part B until the SRC has conducted its review of the first 4 subjects in 
Cohort 3 of Part A.  If CAZ-AVI safety, toleration or PK are not consistent with expectations 
after the first 4 subjects in any Cohort, then it may be necessary to delay or stagger the 
remaining cohorts to gain more experience, in which case an updated Pfizer and EDMC 
approved cohort enrollment sequence will be provided to sites in a written protocol 
Clarification Memorandum.
4.5. Procedures for Handling Incorrectly Enrolled Subjects
Where a subject does not meet all the eligibility criteria, but is enrolled in error and 
incorrectly started on study treatment, the Investigator should inform the Medical Monitor 
immediately, and a discussion should occur between the Medical Monitor and the 
Investigator regarding whether to continue or discontinue the subject from treatment.  The 
Medical Monitor must ensure all decisions are appropriately documented.
4.6. Sponsor’s Qualified Medical Personnel
The contact information for the Sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation at 
each site.


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To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, the subject’s parent(s), legal guardian, or legally acceptable 
representative is provided with a contact card.  The contact card contains, at a minimum, 
protocol and investigational product identifiers, subject study numbers, contact information 
for the Investigator site, and contact details for a contact center in the event that the 
Investigator site staff cannot be reached to provide advice on a medical question or problem 
originating from another healthcare professional not involved in the subject’s participation in 
the study.  The contact number can also be used by Investigator staff if they are seeking 
advice on medical questions or problems; however, it should be used only in the event that 
the established communication pathways between the Investigator site and the study team are 
not available.  It is therefore intended to augment, but not replace, the established 
communication pathways between the Investigator site and the study team for advice on 
medical questions or problems that may arise during the study.  The contact number is not 
intended for use by the subject’s parent(s), legal guardian, or legally acceptable 
representative directly, and if a parent, legal guardian, or legally acceptable representative
calls that number, he or she will be directed back to the Investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33). 
For this study, the investigational product is Zavicefta (ceftazidime-avibactam [CAZ-AVI]).
5.1. Allocation to Treatment
This is an unblinded, single treatment arm study.  All subjects will receive CAZ-AVI.
5.2. Breaking the Blind
This is an open-label study.  Blinding procedures are not applicable.  The Investigator’s 
knowledge of the treatment should not influence the decision to enroll a particular subject or 
affect the order in which subjects are enrolled.
5.3. Subject Compliance
Qualified study center personnel will administer the IV study treatment and assure treatment 
compliance.  At a minimum the dose, date, and exact start and stop time of administration of 
the IV study treatment will be recorded in the appropriate sections of the Case Report Form 
(CRF) and checked by the monitor at monitoring visits.  Deviations from study treatment will 
be reported and documented.


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Subject compliance with dosing administration in Part B will be verified by accounting doses 
administered.  The subject dosing compliance should be within the range of 80% and 
120% of expected doses during the time the subject is receiving IV CAZ-AVI.  Subject 
noncompliance cases should be discussed with medical monitors.
5.4. Investigational Product Supplies
All sites will be provided with an Investigational Product (IP) Manual containing detailed 
instructions on the receipt, storage, dispensing, preparation, and administration of the 
investigational product, as outlined below.  If there is any conflict between this protocol and 
the IP Manual regarding the handling of the investigational product, the IP Manual will take 
precedence.
5.4.1. Dosage Form(s) and Packaging
The investigational product, Zavicefta (ceftazidime 2 g/avibactam 0.5 g), will be supplied by 
Pfizer as a white to yellow powder for concentrate for solution for infusion in a 20 mL glass 
vial.  Each vial contains a fixed dose combination of ceftazidime pentahydrate equivalent to 
2 g ceftazidime and avibactam sodium equivalent to 0.5 g avibactam.
Table 1.
Identity of Investigational Product
Investigational product
Dosage form and strength
Zavicefta (ceftazidime/avibactam)
2 g/0.5 g powder for concentrate for solution for infusion
5.4.2. Preparation and Dispensing
Detailed instructions for the preparation of CAZ-AVI powder for concentrate for solution for 
infusion will be provided in the separate IP Manual.  The investigational product should be 
prepared and dispensed by an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist) as allowed by local, state, and institutional guidance.  The 
preparation and administration of all sterile products must be performed using aseptic 
technique.
Ceftazidime/avibactam powder for concentrate for solution for infusion vials should be 
reconstituted with 10 mL of sterile water for injection.  After reconstitution, 1 mL of solution 
contains 167.3 mg of ceftazidime and 41.8 mg of avibactam.  The reconstituted solution is 
pale yellow and free of particles.  Each vial is for single use only and should be used 
immediately after reconstitution.  The reconstituted solution in the vial should be diluted with
a compatible diluent for administration in an IV bag or IV syringe at the appropriate 
concentration for intravenous infusion.
Any unused product or waste material should be disposed of in accordance with local 
requirements.


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5.5. Administration (Dose and Treatment Regimen)
The prepared doses of CAZ-AVI are intended for intravenous infusion based on age and 
weight as detailed in Table 2.  The dose should generally be calculated based on the subject’s 
first weight of the day on the starting day, although other options such as the birth weight, the 
“dosing weight” or “drug calculation weight” may be used if that is the local standard 
practice for weight-based neonatal drug dosing.  In all situations the weight used for the dose 
calculation must be recorded in the CRF as well as the daily weight on the day dosing is 
started and the daily weight on the day of PK assessment.  Administration should be via 
either an appropriately sized sterile syringe and calibrated syringe pump or IV infusion bag 
and calibrated IV pump over 120 minutes.
Table 2.
CAZ-AVI Weight-based Doses for Each Cohort
Cohort
Age
CAZ-AVI 
weight-based 
dose
Infusion
Volume
Duration
Frequency
1
>28d* to <3m old
30 mg/kg CAZ
7.5 mg/kg AVI
Varies, will 
not exceed 
2 mL/kg/dose
120 min
q8 hr
(Part B 
Only)
2
GA 37wk and 28d old
20 mg/kg CAZ
5.0 mg/kg AVI
3
GA 26wk to <37wk and 28d old
20 mg/kg CAZ
5.0 mg/kg AVI
GA = Gestational Age; d = days; hr = hours; m = month; min = minutes; wk = week.
*Includes term infants (GA 37 weeks) >28 days of age and pre-term infants with corrected age >28 days.  
Corrected age = Subtract the number of weeks born before 40 weeks of gestation from the chronological age 
(Engle, 2004).3
Potential alternative dosing regimens are listed in Appendix 3, which are to be utilized only 
upon written confirmation from the Sponsor that a dosing regimen change is necessary for a 
given cohort or cohorts.  The pharmacokinetics of CAZ-AVI will be evaluated after the first 
4 subjects are enrolled in each age cohort and as necessary the dosing may be adjusted for the 
remaining subjects (see Section 4.4).
5.5.1. Part A
On Day 1 subjects in Part A will receive a single IV infusion of CAZ-AVI over a 2-hour 
(10 min) period according to their cohort as indicated in Table 2.  The infusion can be 
administered any time during the subject’s course of treatment with the other intravenous 
antibiotic, with the exception that no doses of ceftazidime are permitted within 12 hours of 
CAZ-AVI infusion.  The CAZ-AVI infusion should be timed so as to not interfere with 
dosing of the other antibiotic.
5.5.2. Part B 
On Day 1 subjects in Part B will begin receiving IV CAZ-AVI over a 2-hour (10 min) 
period every 8 hours (1 hour) according to their cohort as indicated in Table 2.  The 
CAZ-AVI dose in Part B should not be adjusted based on fluctuations in daily weight, and it 
should remain the same throughout the dosing period up to 14 days, unless local standard 
practice is to reassess all neonatal dosing on a regular basis, such as weekly, and make dose 


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adjustments for weight changes.  In the latter case, CAZ-AVI dosing may be adjusted for 
weight changes, provided PK assessments are not obtained until at least 3 consecutive doses 
are administered after any dose change.  If a subject’s urine output decreases to <0.5 mL/kg/h 
(measured over at least 8 hours) or serum creatinine level increases 2 × ULN during the 
treatment period, the Medical Monitor should be contacted to discuss the subject’s safe 
continuation in the study.  The Investigator should use his or her discretion in determining 
whether a short period of continued observation or discontinuation of therapy is warranted.  
Additionally, in instances of rapidly changing renal function, the Investigator should increase 
the frequency of renal monitoring, depending on the subject’s clinical status, extent of renal 
function change and the Investigator’s clinical evaluation.  Study treatment may be 
temporarily withheld at the discretion of the Investigator.  Subjects withdrawing from study 
therapy can be administered alternative therapies at the Investigator’s choice, which should 
be recorded in the CRF.  If possible, subjects should still be followed for safety.
5.6. Investigational Product Storage 
The Investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.
See the IP manual for storage conditions of the product once reconstituted and/or diluted.
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 


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Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
5.7. Investigational Product Accountability
The Investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
5.7.1. Destruction of Investigational Product Supplies
The Sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the Investigator site, the 
Investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Oral Switch Therapy
Subjects in Part B may be switched to oral therapy after at least 48 hours of IV CAZ-AVI if 
the subject has a good or sufficient clinical response and is tolerating oral fluids or food. The 
decision to switch to oral therapy is entirely at the Investigator’s discretion.  If subjects are 
switched to oral therapy, the End of IV Treatment (EOIV) visit will be conducted at the time 
the intravenous CAZ-AVI study drug is discontinued.  If the subject is discharged from the 
hospital any remaining study visits may be conducted on an outpatient basis.  The choice of 
oral switch therapy, among the options listed below, should be in line with the approved and 
marketed drugs in the respective country, and should observe the local specific regulations 
and local therapeutic guidelines (if existent), regarding posology.  For the optional oral 
switch therapy, the following options are preferred:
1. Oral amoxicillin/clavulanic acid (only in countries where its use for infants/neonates 
is permitted; according to local guidelines, administered at a dose and formulation per 
standard of care), or
2. Oral ciprofloxacin (only in countries where its use for infants/neonates is permitted; 
according to local guidelines, administered at a dose and formulation per standard of 
care) plus metronidazole (administered at a dose and formulation per standard of 
care), or


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3. Pathogen-based therapy (in discussion with the Medical Monitor).  The choice of oral 
antibacterial agent for pathogen-based therapy will be driven by the results of a 
susceptibility test, which will be provided to the Investigator by the local laboratory.  
Initiation of pathogen-based therapy is at the Investigator’s discretion.  Before 
administering pathogen-based therapy, the Investigator will discuss the results of the 
susceptibility test and the selected antibacterial drug (which should be approved for 
use in infants/neonates) with the Medical Monitor.
The optional oral switch therapies will be sourced locally by the study centers or sourced as 
agreed between the study centers and Sponsor.
Consult the Summary of Product Characteristics or product package insert, label, and local 
dosing guidelines for further information regarding dosage, administration, storage, 
maximum doses, contraindications, warnings, precautions, and adverse effects of oral switch 
therapies.
5.9. Intravenous Switch Therapy
In rare situations it may be appropriate to discharge subjects in Part B to continue outpatient 
parenteral antimicrobial therapy (OPAT) at home.  The decision to switch to OPAT is 
entirely at the Investigator’s discretion, but subjects cannot continue to receive the CAZ-AVI 
study drug outside the hospital.  If subjects are candidates for OPAT after at least 48 hours of 
IV CAZ-AVI, Investigators will select the appropriate intravenous antibiotic(s) based on 
culture results, local therapeutic guidelines, and approved and marketed drugs in their 
respective countries.  If subjects are switched to OPAT, the End of IV Treatment (EOIV) 
visit will be conducted at the time the intravenous CAZ-AVI study drug is discontinued.  
After subjects on OPAT are discharged from the hospital any remaining study visits may be 
conducted on an outpatient basis.
The OPAT therapies will be sourced locally by the study centers or sourced as agreed 
between the study centers and Sponsor.  Consult the Summary of Product Characteristics or 
product package insert, label, and local dosing guidelines for further information regarding 
dosage, administration, storage, maximum doses, contraindications, warnings, precautions, 
and adverse effects of OPAT therapies.
5.10. Concomitant Treatment(s)
Use of potent inhibitors of organic anion transporters OAT1 and/or OAT3 (eg, probenecid, 
p-aminohippuric acid (PAH), or teriflunomide) are prohibited during the study because they 
have the potential to alter (decrease) the clearance of avibactam when coadministered.  This 
prohibition on the use of OAT1 and/or OAT3 inhibitors also applies to the mothers of any 
neonates or infants who are breast feeding during the trial. 
Intravenous treatment with chloramphenicol during the study is prohibited within 24 hours of 
administration of study doses of CAZ-AVI in Part B.  Chloramphenicol is antagonistic in 
vitro with ceftazidime and other cephalosporins, though the clinical relevance of this finding 
is not known.


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Concomitant treatment with ceftazidime is not permitted any time during the study or within 
12 hours of CAZ-AVI administration.
In Part A, the use of any other antibiotics is permitted, including other antibiotics combined 
with beta lactamase inhibitors. In Part B, the use of antibiotics combined with other beta 
lactamase inhibitors is prohibited, including combinations with the beta lactamase inhibitors 
sulbactam, tazobactam, clavulanate, and any new beta lactamase inhibitors which become 
available during the course of the study.
Adjunctive IV antibacterial treatment for suspected co-infection with Gram-positive 
organisms may be given per standard of care, with preference for ampicillin or vancomycin.  
If Gram-positive coverage is added empirically and subsequent culture results do not isolate 
a Gram-positive pathogen, the Investigator should consider discontinuing the additional 
Gram-positive coverage.  Metronidazole may be added to CAZ-AVI to provide coverage for 
anaerobic organisms.  Adjunctive coverage for aerobic Gram-negative organisms is 
discouraged, but if additional coverage against multi-drug resistant Gram-negative organisms 
is empirically indicated to ensure adequate therapy while awaiting baseline culture and 
susceptibility results, additional Gram-negative coverage with aminoglycosides gentamicin 
or amikacin may be added per standard of care.
Consult the Summary of Product Characteristics, product package insert, label, and local 
dosing guidelines for information regarding dosage, administration, storage, maximum doses, 
contraindications, warnings, precautions, and adverse effects for adjunctive antibacterial 
treatment.
6. STUDY PROCEDURES
Study periods are defined in Figure 1.  Details of the study plan and procedures are provided 
in the SCHEDULE OF ACTIVITIES and are described in detail by visit in the following 
sections.
6.1. Screening and Enrollment
Prior to any study specific procedures, the subject’s parent or parents (depending on local 
requirements) or legally acceptable representative must provide written informed consent.  
During the screening period, subjects will be assessed regarding eligibility criteria.  Subjects 
who do not meet all of these criteria must not be enrolled in the study.
6.1.1. Visit 1: Eligibility/Screening Procedures (Day -1 to 1)
Each subject will undergo Screening assessment procedures on the day of or one day prior to 
the first dose of CAZ-AVI as outlined in the SCHEDULE OF ACTIVITIES.  Screening 
assessments can serve as baseline if they are completed on the same calendar day as Day 1, 
prior to CAZ-AVI infusion, but they must be completed no earlier than the day before the 
start of CAZ-AVI infusion, except for laboratory assessments in Part A which may be up to 
2 days before the start of CAZ-AVI infusion.  If additional assessments are conducted per 
standard of care prior to the first infusion of CAZ-AVI the assessments closest to the infusion 
will be considered baseline.  Potential subjects who do not meet enrollment criteria may, as 
appropriate, repeat screening evaluations at a later time for possible enrollment into the 
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6.1.1.1. Clinical Assessments
1. Obtain informed consent.
2. Review the inclusion and exclusion criteria.
3. Obtain a complete medical history, including, but not limited to, history of delivery, 
antepartum and peripartum antibacterials, vaccinations, congenital abnormalities, 
surgeries, and all conditions diagnosed after birth.
4. Record demography.
5. Identify, assess, and record any new or ongoing Adverse Events (AEs) or Serious 
Adverse Events (SAEs).
6. Review and record prior and concomitant medications taken or received within 7 days 
before the first dose of study therapy, including, but not limited to, all antimicrobials, 
parenteral nutrition, and blood and blood component transfusions.  For subjects who 
are being breast fed, record all medications taken by the lactating mother during the 
3 days before the first dose of study therapy.
7. Perform brief physical examination, including, but not limited to:
a.
Physical findings related to bacterial infection or sepsis;
b. Presence of central venous catheter (eg, umbilical catheter);
c.
Presence of other medical devices such as ventilator, cardiac devices, 
cerebrospinal fluid (CSF) shunts, orthopedic transplants, or urinary catheter.
8. Record weight and length.
9. Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation:
a.
Record at least 2 heart rate/pulse measurements taken during a 30 minute period.
b. Record at least 2 blood pressure measurements, or record highest and lowest 
measurements if continuously monitored, over a 30 minute period.
10. Record imaging study results (eg, chest x-ray, echocardiogram, computerized 
tomography scan (CT scan), magnetic resonance imaging (MRI), ultrasound) if 
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6.1.1.2. Laboratory Assessments
1. Obtain blood samples for complete blood count (CBC) with differential and 
chemistry panel (see Laboratory Manual).  For Part A, if the subject is improving and 
laboratory assessments were performed within 2 days of CAZ-AVI infusion, those 
test results may be used for eligibility and they do not need to be repeated for 
screening.
2. If clinically indicated and if blood gases are available (Part B Only), calculate base 
excess (BE) using the formula:
BE = 0.02786 * pCO2 * 10(pH - 6.1) + 13.77 * pH - 124.58
pCO2 = partial pressure of carbon dioxide (mm Hg).
pH = negative logarithm of the hydrogen ion concentration (a measure of acidity or 
alkalinity).
3. If clinically indicated, record CRP and serum procalcitonin levels if tests are 
performed as part of the subject’s regular medical care (Part B Only).
4. Perform urinalysis (see Laboratory Manual).
5. For subjects who have been hospitalized for 8 hours, calculate urine output over the 
last 8 hour period.
6.1.1.3. Microbiological Assessments (Part B Only)
1. If clinically indicated and performed as part of subject’s regular medical care, obtain 
blood culture for testing per Section 7.3.1; cultures should be repeated per standard of 
care upon knowledge of a positive result until sterilization is confirmed.
2. If clinically indicated, obtain urine culture for testing per Section 7.3.2; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed.
3. If clinically indicated and performed as part of subject’s regular medical care, obtain 
other specimens/tissue samples per Section 7.3.3; cultures should be repeated per 
standard of care upon knowledge of a positive result.
4. Obtain any prior microbiological and clinical data (eg, notes in medical records 
confirming worsening of signs and symptoms of infection) that may help determine 
eligibility.
Enroll the subject after verifying that the subject meets all inclusion and no exclusion criteria.  
There should be no medically inappropriate delay in administration of study therapy.


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6.2. Study Period
6.2.1. Visit 2, Study Day 1
Study Day 1 is the day of the first administration of study therapy.
6.2.1.1. Study Therapy Administration
1. Infusion of CAZ-AVI IV over a 2-hour (10 min) period, according to the cohort as 
indicated in Table 2.  The dose should be calculated based on the subject’s first 
weight of the day on the starting day unless the local standard practice for neonatal 
weight-based dosing is to use an alternative weight, such as the birth weight (see 
Section 5.5).  For subjects in Part A this will be the only infusion of CAZ-AVI.  
Subjects in Part B will continue CAZ-AVI infusions every 8 hours. The CAZ-AVI 
dose in Part B should not be adjusted based on fluctuations in daily weight, and it 
should remain the same throughout the dosing period up to 14 days, unless local 
standard practice is to reassess all neonatal dosing on a regular basis, such as weekly, 
and make dose adjustments for weight changes.  In the latter case, CAZ-AVI dosing 
may be adjusted for weight changes, provided PK assessments are not obtained until 
at least 3 consecutive doses are administered after any dose change.
2. Part B Only: Optional antibacterial coverage for Gram-positive organisms, dosage per 
institutional guidelines and Investigator’s judgement.  IV ampicillin or vancomycin 
are preferred, but choice of therapy is at the Investigator’s discretion.
3. Part B Only: Optional IV aminoglycoside, gentamicin or amikacin, if additional 
coverage against multi-drug resistant (MDR) Gram-negative organisms is empirically 
indicated to ensure adequate therapy while awaiting baseline culture and 
susceptibility results.  Choice of aminoglycoside and dosage are per institutional 
guidelines and Investigator’s judgement.
4. Part B Only: Optional IV metronidazole for anaerobes: dosage per institutional 
guidelines and Investigator’s judgement.
6.2.1.2. Clinical Assessments
1. Identify, assess, and record any new or ongoing AEs or SAEs.
2. Record concomitant medications including, but not limited to, all antimicrobials, 
parenteral nutrition, and blood and blood component transfusions.  For subjects who 
are being breast fed, record all medications taken by the lactating mother.
3. Prior to the start of the infusion, record the findings of a brief physical examination, 
including, but not limited to, physical findings of infection or sepsis, presence of 
central venous catheter or other medical devices (if applicable).
4. Record the subject’s first weight of the day.


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5. Prior to the start of the infusion, record vital signs (heart rate/pulse, blood pressure, 
respiratory rate, temperature) and oxygen saturation (if available); record the daily 
highest and lowest temperature measurements.
6. Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed.
7. If clinically indicated, obtain results of chest x-ray (CXR), CT scan, or other imaging 
tests performed as part of the subject’s regular medical care.
6.2.1.3. Laboratory Assessments
1. If clinically indicated, prior to the start of the infusion, obtain blood samples for CBC 
with differential and chemistry panel (see Laboratory Manual).
2. Part B Only: If clinically indicated and if blood gases are available, calculate base 
excess (BE) using the formula:
BE = 0.02786 * pCO2 * 10(pH - 6.1) + 13.77 * pH - 124.58
3. Part B Only: If clinically indicated, obtain CRP and serum procalcitonin levels.
4. If clinically indicated, prior to the start of the infusion, perform urinalysis 
(see Laboratory Manual).
5. Calculate urine output over the last 8 hour period.
6.2.1.4. Microbiological Assessments (Part B Only)
1. If clinically indicated and performed as part of subject’s regular medical care, obtain 
blood culture for testing per Section 7.3.1; cultures should be repeated per standard of 
care upon knowledge of a positive result until sterilization is confirmed.
2. If clinically indicated, obtain urine culture for testing per Section 7.3.2; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed.
3. If clinically indicated and performed as part of subject’s regular medical care, obtain 
other specimens/tissue samples per Section 7.3.3; cultures should be repeated per 
standard of care upon knowledge of a positive result.
6.2.1.5. PK Procedures – Part A Only
Following the infusion of CAZ-AVI, blood samples for PK (0.3 mL per sample) will be 
collected at the following time points: 1) anytime within 15 minutes after stopping CAZ-AVI 
infusion, 2) anytime between 30 minutes and 90 minutes after stopping CAZ-AVI infusion, 
and 3) anytime between 300 minutes (5 hours) and 360 minutes (6 hours) after stopping 
CAZ-AVI infusion.  If the dosing interval for any cohort is increased from every 8 hours to 
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540 minutes (9 hours) and 600 minutes (10 hours) after stopping CAZ-AVI infusion.  
Preference should be given to the first and last collection time if only two PK samples are 
obtained.  For infants weighing less than 1 kg only the first and third PK blood sample will 
be collected.  PK blood samples are NOT to be drawn if the subject received a blood or blood 
component transfusion within the past 24 hours.  For subjects who are at risk from additional 
blood loss, collection of PK samples will require assessment by the Investigator.
6.2.2. Visit 3, Study Day 2: Part A Only
6.2.2.1. Clinical Assessments
1. Identify, assess, and record any new or ongoing AEs or SAEs.
2. Record concomitant medications including, but not limited to, all antimicrobials, 
parenteral nutrition, and blood and blood component transfusions.  For subjects who 
are being breast fed, record all medications taken by the lactating mother.
3. Record the findings of a brief physical examination, including, but not limited to, 
physical findings of infection or sepsis, presence of central venous catheter or other 
medical devices (if applicable).
4. Record the subject’s first weight of the day.
5. Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record the daily highest and lowest temperature measurements.
6. Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed.
7. If clinically indicated, obtain results of CXR, CT scan, or other imaging tests 
performed as part of the subject’s regular medical care.
6.2.2.2. Laboratory Assessments
1. Obtain blood samples for complete blood count (CBC) with differential and 
chemistry panel (see Laboratory Manual).
2. Perform urinalysis (see Laboratory Manual).
3. Calculate urine output over the last 8 hour period.
6.2.3. Visit 4, Study Day 3: Part A Only
6.2.3.1. Clinical Assessments
1. Identify, assess, and record any new or ongoing AEs or SAEs.
2. Record concomitant medications including, but not limited to, all antimicrobials, 
parenteral nutrition, and blood and blood component transfusions.  For subjects who 
are being breast fed, record all medications taken by the lactating mother.


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3. Record the findings of a brief physical examination, including, but not limited to, 
physical findings of infection or sepsis, presence of central venous catheter or other 
medical devices (if applicable).
4. Record the subject’s first weight of the day.
5. Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record the daily highest and lowest temperature measurements.
6. Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed.
7. If clinically indicated, obtain results of CXR, CT scan, or other imaging tests 
performed as part of the subject’s regular medical care.
6.2.3.2. Laboratory Assessments
1. If clinically indicated, obtain blood samples for complete blood count (CBC) with 
differential and chemistry panel (see Laboratory Manual).
2. If clinically indicated, perform urinalysis (see Laboratory Manual).
6.2.4. Visits 3-15, Study Days 2-14: Part B Only
6.2.4.1. Study Therapy Administration
1. Infusion of CAZ-AVI IV over a 2-hour (10 min) period q8h, according to the cohort 
as indicated in Table 2.  The CAZ-AVI dose in Part B should not be adjusted based 
on fluctuations in daily weight, and it should remain the same throughout the dosing 
period up to 14 days, unless local standard practice is to reassess all neonatal dosing 
on a regular basis, such as weekly, and make dose adjustments for weight changes.  In 
the latter case, CAZ-AVI dosing may be adjusted for weight changes, provided PK 
assessments are not obtained until at least 3 consecutive doses are administered after 
any dose change.
2. Antibacterial coverage for Gram-positive organisms, an aminoglycoside for 
additional MDR Gram-negative coverage, or metronidazole for anaerobes is 
considered optional beginning on Day 1 through the entire study at a dosage per 
institutional guidelines and Investigator’s judgement.  These optional IV 
antibacterials may be started and stopped at any time during the study at the 
discretion of the Investigator.
6.2.4.2. Clinical Assessments
1. Identify, assess, and record any new or ongoing AEs or SAEs.
2. Record concomitant medications including, but not limited to, all antimicrobials, 
parenteral nutrition, and blood and blood component transfusions.  For subjects who 
are being breast fed, record all medications taken by the lactating mother.


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3. Record the findings of a brief physical examination, including, but not limited to, 
physical findings of infection or sepsis, presence of central venous catheter or other 
medical devices (if applicable).
4. Record the subject’s first weight of the day.
5. Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record the daily highest and lowest temperature measurements.
6. Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed.
7. If clinically indicated, obtain results of CXR, CT scan, or other imaging tests 
performed as part of the subject’s regular medical care.
6.2.4.3. Laboratory Assessments
1. If clinically indicated, obtain blood samples for CBC with differential and chemistry 
panel (see Laboratory Manual).
2. If clinically indicated and if blood gases are available, calculate base excess (BE) 
using the formula:
BE = 0.02786 * pCO2 * 10(pH - 6.1) + 13.77 * pH - 124.58
3. If clinically indicated, obtain CRP and serum procalcitonin levels.
4. If clinically indicated, perform urinalysis (see Laboratory Manual).
5. Calculate urine output over the last 8 hour period.
6.2.4.4. Microbiological Assessments
1. If clinically indicated and performed as part of subject’s regular medical care, obtain 
blood culture for testing per Section 7.3.1; cultures should be repeated per standard of 
care upon knowledge of a positive result until sterilization is confirmed.
2. If clinically indicated, obtain urine culture for testing per Section 7.3.2; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed.
3. If clinically indicated and performed as part of subject’s regular medical care, obtain 
other specimens/tissue samples per Section 7.3.3; cultures should be repeated per 
standard of care upon knowledge of a positive result.


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6.2.4.5. PK Procedures
Do not draw PK blood samples if the subject received a blood or blood component 
transfusion within the past 24 hours.  For subjects who are at risk from additional blood loss, 
collection of PK samples will require assessment by the Investigator.
Obtain 3 single PK blood samples between the end of the third consecutive infusion and
before EOIV or Study Day 14 (whichever is earlier).  Each sample is 0.3 mL (2 x 0.3 mL for 
premature infants weighing less than 1 kg).  Collection times relative to the start of the 
infusion are: (1) within 15 minutes after stopping CAZ-AVI infusion, (2) between 30 minutes 
and 90 minutes after stopping the infusion, and (3) between 300 min (5 hours) and 
360 minutes (6 hours) after stopping the infusion.  If the dosing interval for any cohort is 
increased from every 8 hour to every 12 hours, then timing of the third PK sample will be 
changed to anytime between 540 minutes (9 hours) and 600 minutes (10 hours) after stopping 
CAZ-AVI infusion.  Preference should be given to the first and last collection time if only 
two PK samples are obtained.  For infants weighing less than 1 kg only the first and third PK 
blood sample will be collected.
6.2.5. End of IV (EOIV): Part B Only
EOIV assessments should be performed within 24 hours after completion of the last infusion 
of CAZ-AVI or at the time of premature discontinuation of CAZ-AVI or early withdrawal 
from study (if on IV therapy).  The EOIV assessments should be conducted in place of the 
regular study visit (eg, Days 2 to 15) assessments that would have been performed the day 
of that visit.  Study therapy may or may not be given on the same calendar day as EOIV 
assessments.  A subject may be eligible to switch to oral therapy on or after at least 48 hours 
of IV CAZ-AVI (Section 5.8).  EOIV assessments must occur before starting oral switch 
therapy.  If a subject is not switched to oral therapy then the EOIV assessment also serves as 
the EOT assessment.  The following will be performed:
6.2.5.1. Clinical Assessments
1. Identify, assess, and record any new or ongoing AEs or SAEs.
2. Record concomitant medications including, but not limited to, all antimicrobials, 
parenteral nutrition, and blood and blood component transfusions.  For subjects who 
are being breast fed, record all medications taken by the lactating mother.
3. Record the findings of a brief physical examination, including, but not limited to, 
physical findings of infection or sepsis, presence of central venous catheter or other 
medical devices (if applicable).
4. Record the subject’s first weight of the day.
5. Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record the daily highest and lowest temperature measurements.


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6. Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed.
7. If clinically indicated, obtain results of CXR, CT scan, or other imaging tests 
performed as part of the subject’s regular medical care.
8. Assessment of clinical outcome by the Investigator (Table 5).
6.2.5.2. Laboratory Assessments
1. Obtain blood samples for complete blood count (CBC) with differential and 
chemistry panel (see Laboratory Manual).
2. If clinically indicated and if blood gases are available, calculate base excess (BE) 
using the formula:
BE = 0.02786 * pCO2 * 10(pH - 6.1) + 13.77 * pH - 124.58
3. If clinically indicated record CRP and serum procalcitonin levels if tests are 
performed as part of the subject’s regular medical care.
4. Perform urinalysis (see Laboratory Manual).
5. Calculate urine output over the last 8 hour period.
6.2.5.3. Oral Switch Therapy Administration
Administer oral switch therapy as appropriate per Investigator discretion.
6.2.5.4. Microbiological Assessments
1. If clinically indicated and performed as part of subject’s regular medical care, obtain 
blood culture for testing per Section 7.3.1; cultures should be repeated per standard of 
care upon knowledge of a positive result until sterilization is confirmed.
2. If clinically indicated, obtain urine culture for testing per Section 7.3.2; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed.
3. If clinically indicated and performed as part of subject’s regular medical care, obtain 
other specimens/tissue samples per Section 7.3.3; cultures should be repeated per 
standard of care upon knowledge of a positive result.
6.2.6. End of Treatment (Oral or OPAT): Part B Only
The assessments at EOT should be performed within 48 hours after the last dose of oral or 
OPAT switch therapy or at the time of premature discontinuation of oral or OPAT switch 
therapy or early withdrawal from study (if on oral or OPAT switch therapy).  If a subject 
does not switch to oral or OPAT therapy, the EOIV assessments for IV CAZ-AVI also serve 
as the EOT assessments.  For subjects receiving oral or OPAT switch therapy only, the 


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following will be performed.  If a subject was previously assessed as a clinical failure, only 
the safety assessments need to be performed (ie, AEs and SAEs, concomitant medications, 
adjunctive therapeutic procedures, weight, vital signs, CBC with differential and chemistry 
panel if clinically indicated and performed as part of subject's regular medical care).
1. Identify, assess, and record any new or ongoing AEs or SAEs.
2. Record concomitant medications including, but not limited to, all antimicrobials, 
parenteral nutrition, and blood and blood component transfusions.  For subjects who 
are being breast fed, record all medications taken by the lactating mother.
3. Record the findings of a brief physical examination, including, but not limited to, 
physical findings of infection or sepsis, presence of central venous catheter or other 
medical devices (if applicable).
4. Record the subject’s first weight of the day.
5. Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record the daily highest and lowest temperature measurements.
6. Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed.
7. If clinically indicated, obtain results of CXR, CT scan, or other imaging tests 
performed as part of the subject’s regular medical care.
8. Assessment of clinical outcome by the Investigator (Table 5).
6.2.6.1. Laboratory Assessments
1. If clinically indicated, obtain blood samples for complete blood count (CBC) with 
differential and chemistry panel (see Laboratory Manual).
2. If clinically indicated and if blood gases are available, calculate base excess (BE) 
using the formula:
BE = 0.02786 * pCO2 * 10(pH - 6.1) + 13.77 * pH - 124.58
3. If clinically indicated, record CRP and serum procalcitonin levels if tests are 
performed as part of the subject’s regular medical care.
4. If clinically indicated, perform urinalysis (see Laboratory Manual).
5. If clinically indicated, calculate urine output over the last 8 hour period.
6.2.6.2. Microbiological Assessments
1. If clinically indicated and performed as part of subject’s regular medical care, obtain 
blood culture for testing per Section 7.3.1; cultures should be repeated per standard of 
care upon knowledge of a positive result until sterilization is confirmed.


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2. If clinically indicated, obtain urine culture for testing per Section 7.3.2; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed.
3. If clinically indicated and performed as part of subject’s regular medical care, obtain 
other specimens/tissue samples per Section 7.3.3; cultures should be repeated per 
standard of care upon knowledge of a positive result.
6.2.7. Test of Cure (TOC): Part B Only
Conduct TOC assessments 7 to 14 days after administration of the last dose of study therapy 
(IV or oral).  If a subject was previously assessed as a clinical failure, only the safety 
assessments need to be performed (ie, AEs and SAEs, concomitant medications, adjunctive 
therapeutic procedures, weight, vital signs, CBC with differential and chemistry panel if 
clinically indicated and performed as part of subject's regular medical care).
6.2.7.1. Clinical Assessments
1. Identify, assess, and record any new or ongoing AEs or SAEs.
2. Record concomitant medications including, but not limited to, all antimicrobials, 
parenteral nutrition, and blood and blood component transfusions.  For subjects who 
are being breast fed, record all medications taken by the lactating mother.
3. Record the findings of a brief physical examination, including, but not limited to, 
physical findings of infection or sepsis, presence of central venous catheter or other 
medical devices (if applicable).
4. Record the subject’s first weight of the day.
5. Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record the daily highest and lowest temperature measurements.
6. Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed.
7. If clinically indicated, obtain results of CXR, CT scan, or other imaging tests 
performed as part of the subject’s regular medical care.
8. Assessment of clinical outcome by the Investigator (Table 5).
6.2.7.2. Laboratory Assessments
1. If clinically indicated, obtain blood samples for CBC with differential and chemistry 
panel (see Laboratory Manual).
2. If clinically indicated, perform urinalysis (see Laboratory Manual).
3. If clinically indicated, calculate urinary output over the last 8 hour period.


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6.2.7.3. Microbiological Assessments
1. If clinically indicated and performed as part of subject’s regular medical care, obtain 
blood culture for testing per Section 7.3.1; cultures should be repeated per standard of 
care upon knowledge of a positive result until sterilization is confirmed.
2. If clinically indicated, obtain urine culture for testing per Section 7.3.2; cultures 
should be repeated per standard of care upon knowledge of a positive result until 
sterilization is confirmed.
3. If clinically indicated and performed as part of subject’s regular medical care, obtain 
other specimens/tissue samples per Section 7.3.3; cultures should be repeated per 
standard of care upon knowledge of a positive result.
6.2.8. Late Follow-Up (LFU)
6.2.8.1. Part A
Follow-up contact will be completed at least 28 calendar days, and up to 35 calendar days 
after infusion of CAZ-AVI to capture any potential adverse events or serious adverse events.  
Contact with the subject’s parent(s)/legal guardian/legally acceptable representative may be 
conducted via a telephone call.
6.2.8.2. Part B
Conduct LFU assessments, preferably in person, 28 to 35 days after the last dose of 
IV CAZ-AVI.  The LFU may be conducted via telephone for any subject who has not 
experienced clinical relapse, did not have ongoing AEs or SAEs at TOC, or did not develop 
AEs or SAEs since TOC.  If symptoms of relapse or new AEs or SAEs are noted, or at the 
discretion of the Investigator, the subject should be immediately scheduled for an in person 
visit.  If a subject was previously assessed as a clinical failure, only the safety assessments 
need to be performed (ie, AEs and SAEs, concomitant medications, adjunctive therapeutic 
procedures, weight, vital signs, CBC with differential and chemistry panel if clinically 
indicated and performed as part of subject's regular medical care).
1. Identify, assess, and record any new or ongoing AEs or SAEs.
2. Record concomitant medications including, but not limited to, all antimicrobials, 
parenteral nutrition, and blood and blood component transfusions.  For subjects who 
are being breast fed, record all medications taken by the lactating mother.
3. Record the findings of a brief physical examination, including, but not limited to, 
physical findings of infection or sepsis, presence of central venous catheter or other 
medical devices (if applicable).
4. Record weight.
5. Record vital signs (heart rate/pulse, blood pressure, respiratory rate, temperature) and 
oxygen saturation; record highest and lowest daily temperature measurements.


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6. Record adjunctive therapeutic procedures (eg, drainage of foci of infection), if 
performed.
7. If clinically indicated, obtain blood samples for CBC with differential and chemistry 
panel (see Laboratory Manual).
8. If clinically indicated, perform urinalysis (see Laboratory Manual).
9. Assessment of clinical outcome by the Investigator (Table 5).  The clinical outcome 
assessed at this visit is for relapse or potential re-infection.
6.3. Subject Withdrawal [Early Termination]
Withdrawal of Consent:
Subjects whose parent(s)/legal guardian/legally acceptable representative request to 
discontinue receipt of study treatment will remain in the study and must continue to be 
followed for protocol specified follow-up procedures.  The only exception to this is when a 
subject’s parent(s)/legal guardian/legally acceptable representative specifically withdraws 
consent for any further contact with the subject, themselves or persons previously authorized 
to provide this information.  Subject’s parent(s)/legal guardian/legally acceptable 
representative should notify the Investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the Investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate CRF page.  In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to Follow-Up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  Lost 
to follow-up is defined by the inability to reach the subject’s parent(s)/legal guardian/legally 
acceptable representative after a minimum of 2 documented phone calls, faxes, or e-mails as 
well as lack of response by the subject’s parent(s)/legal guardian/legally acceptable 
representative to 1 registered mail letter.  All attempts should be documented in the subject’s 
medical records.  If it is determined that the subject has died, the site will use locally 
permissible methods to obtain the date and cause of death.  If the Investigator’s use of a 
third-party representative to assist in the follow-up portion of the study has been included in 
the subject’s informed consent, then the Investigator may use a Sponsor-retained third-party 
representative to assist site staff with obtaining the subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study.  The site 
staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If, after all attempts, 
the subject remains lost to follow-up, then the last-known-alive date as determined by the 
Investigator should be reported and documented in the subject’s medical records.


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Subjects may withdraw from the study at any time at the request of their parent(s)/legal 
guardian/legally acceptable representative, or they may be withdrawn at any time at the 
discretion of the Investigator or Sponsor for safety (see also the Withdrawal From the Study 
Due to Adverse Events section) or behavioral reasons, or the inability of the subject to 
comply with the protocol-required schedule of study visits or procedures at a given study 
site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject’s parent(s)/legal guardian/legally acceptable representative.  All attempts to contact 
the subject’s parent(s)/legal guardian/legally acceptable representative and information 
received during contact attempts must be documented in the subject’s medical record.  In any 
circumstance, every effort should be made to document subject outcome, if possible.  The 
Investigator should inquire about the reason for withdrawal, request that the subject return for 
a final visit, if applicable, and follow up with the subject’s parent(s)/legal guardian/legally 
acceptable representative regarding any unresolved adverse events (AEs).
If the subject’s parent(s)/legal guardian/legally acceptable representative withdraws the 
subject from the study, and also withdraws consent for disclosure of future information, no 
further evaluations should be performed, and no additional data should be collected.  The 
Sponsor may retain and continue to use any data collected before such withdrawal of 
consent.
Subjects who withdraw from the study may be replaced at the discretion of the Investigator 
upon consultation with the Sponsor. 
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the Investigator that may make it unfeasible to 
perform the test.  In these cases the Investigator will take all steps necessary to ensure the 
safety and well-being of the subject.  When a protocol-required test cannot be performed, the 
Investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the Investigator site prior 
to initiation of the study.
7.1. Pharmacokinetics 
7.1.1. Plasma for Analysis of Ceftazidime - Avibactam
Blood samples (0.3 mL) to provide approximately 0.15 mL of plasma for pharmacokinetic 
(PK) analysis will be collected into appropriately labeled tubes containing Sodium 
Fluoride/Potassium Oxalate (custom blue top) at times as shown in Figure 3 and specified in 
the SCHEDULE OF ACTIVITIES.  Venous PK blood samples may be obtained by 


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venipuncture, through a saline/heparin lock, peripherally inserted central catheter, or through 
a central line or umbilical vein catheter.  Arterial blood sources are not acceptable for PK 
blood samples.  Capillary blood from a heel stick may be utilized if a venous blood sample is 
not reasonably obtainable.  Except for the PK sample to be obtained immediately after the 
end of the infusion, samples may be drawn from the infusion site only if a multi-lumen 
catheter is used and these samples must be drawn through a lumen that was not used to 
deliver drug. PK samples taken immediately after the end of the infusion must not be taken 
from the infusion site, regardless of whether a multi-lumen catheter is used or not.
Sample collection and handling details are provided in the Laboratory Manual.  PK blood 
samples are NOT to be drawn if the subject received a blood or blood component transfusion 
within the past 24 hours.  For subjects who are at risk from additional blood loss, collection 
of PK samples will require assessment by the Investigator.
Figure 3.
Pharmacokinetic CAZ-AVI Sample Collection Time Points
Sample
1       2
     3
120 minute infusion
Time
0
1
2
3
4
5
6
7
8    hours
All subjects (3 samples/subject)a
Sample 1
Within 15 minutes after stopping infusion.
Sample 2
Between 30 minutes and 90 minutes after stopping the infusion.
Sample 3
Between 300 min (5 hours) and 360 minutes (6 hours) after stopping the 
infusion.b
Part A
PK samples will be collected after a single dose of CAZ-AVI has been infused.
Part B
PK samples will be collected after at least 3 consecutive doses of CAZ-AVI 
have been infused.
Abbreviations: CAZ-AVI = ceftazidime-avibactam; PK = pharmacokinetic.
a.
For infants weighing less than 1 kg only the first and third PK blood sample will be collected.  If only 2 PK 
samples are collected for any reason, preference should be given to the first and third collection time.
b.
If the dosing interval for any cohort is increased from every 8 hour to every 12 hours in the study, then 
timing of the third PK sample will be changed to anytime between 540 minutes (9 hours) and 600 minutes 
(10 hours) after stopping CAZ-AVI infusion.
The date, starting and stop time of infusion and exact time of sample collection must be 
recorded in the CRF for each sample.  By convention, the PK sample collection times in the 
CRF are specified by the nominal sampling time relative to the infusion start, as shown on 
the ordinate of Figure 3.  The first PK sample collected within 15 minutes of stopping the 


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infusion has a nominal sampling time of 2 hours, the second PK sample has a nominal 
sampling time of 2 hours and 30 minutes, and the third sample has a nominal sampling time 
of 7 hours (or 11 hours if the dosing interval is increased to every 12 hours). If a deviation 
from the protocol is experienced due to technical difficulties, eg, with the administration of 
the infusion or PK sampling, the details of the deviation have to be recorded in the CRF.
All efforts will be made to obtain the PK samples within the PK sampling time windows 
relative to stopping the infusion. 
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer/vendor standard operating procedures (SOPs).
The PK samples must be processed and shipped as indicated in the instructions provided to 
the Investigator site to maintain sample integrity.  Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the Sponsor.  
On a case-by-case basis, the Sponsor may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation.
As part of understanding the PK of the investigational product, samples may be used for 
evaluation of the bioanalytical method, as well as for other internal exploratory purposes.  
Leftover plasma could be used to assess concentrations of endogenous biomarkers for drug 
transporters and/or drug metabolizing enzymes.  These data will not be included in the CSR.  
7.2. Banked Biospecimens 
Not applicable.
7.2.1. Additional Research 
Not applicable.
7.3. Microbiology
7.3.1. Blood Sample for Culture
If clinically indicated and performed as part of subject’s regular medical care, obtain blood 
for culture at Baseline (preferably before any antibacterials are administered) and at any time 
through TOC.  Cultures should be repeated per standard of care upon knowledge of a positive 
result until sterilization is confirmed.  Perform culture and organism identification at the local 
or regional laboratory, as applicable.  Send all isolates to the central laboratory for organism 
identification and susceptibility testing.
Refer to the study specific clinical and microbiology laboratory manual for specific 
procedures pertaining to the collection, processing, storage, and shipment of blood culture or 
isolates.


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7.3.2. Urine Sample for Culture
If clinically indicated per standard of care, obtain urine for culture at Baseline (preferably 
before any antibacterials are administered) and at any time through TOC.  Cultures should be 
repeated per standard of care upon knowledge of a positive result until sterilization is 
confirmed.  Perform Gram stain, culture, and organism identification at the local or regional
laboratory, as applicable.  Send all isolates to the central laboratory for organism 
identification and susceptibility testing.
Refer to the study specific clinical and microbiology laboratory manual for specific 
procedures pertaining to the collection, processing, storage, and shipment of urine culture or 
isolates.
7.3.3. Other Specimens and Tissue Samples for Culture
If clinically indicated and performed as part of subject’s regular medical care, obtain other 
specimen and tissue samples from potential foci of infection for culture as clinically 
indicated at Baseline (preferably before any antibiotics are administered) and at any time 
through TOC.  Cultures should be repeated per standard of care upon knowledge of a positive 
result.  Perform Gram stain (if applicable), culture, and organism identification at the local or 
regional laboratory.  Send all isolates to the central laboratory for organism identification and 
susceptibility testing.
Refer to the study specific microbiology and clinic laboratory manual for specific procedures 
pertaining to the collection, processing, storage, and shipment of other specimens/tissues for 
culture or isolates.
7.4. Safety Assessments
Subjects must be evaluated by a physician or an appropriately trained health care 
professional at every visit, and the evaluation must be documented.  The procedures 
discussed below will be completed at the designated visits.
7.4.1. Laboratory Safety Assessments
Blood samples and urine samples will be collected at screening baseline and EOIV, if 
applicable.  Samples may also be collected at any time during the treatment period, at TOC 
and LFU if clinically indicated.


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The following laboratory variables will be measured:
Table 3.
Laboratory Safety Variables
Chemistry panel
Hematology panel
Urinalysis
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Bilirubin, total and direct
Blood urea nitrogen/urea
Calcium
Chloride
Creatinine
Glucose, nonfastinga
Potassium
Sodium
Bicarbonate (HCO3)a
Lactatea
pHa
C reactive proteina
Procalcitonina
Hematocrit
Hemoglobin
Red Blood Cell count
White Blood Cell count
Eosinophilsb
Lymphocytesb
Monocytesb
Neutrophilsb
Neutrophils, immatureb
Platelets
Appearance (color, clarity)
Bilirubin
Glucose
Ketones
Leukocyte esterase
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Alkaline phosphatase
a.
Test may be used for eligibility, but is not mandatory for eligibility if other eligibility criteria are met.
b.
Absolute count and/or %.
7.5. Blood Volume
This protocol complies with European Union’s recommendations for blood loss associated 
with pediatric research (Anonymous, 2017)7 and the World Health Organization guidelines 
“Blood Sample Volumes in Child Health Research: Review of Safe Limits” (Howie, 2011).8  
To minimize risk from blood loss associated with this study, standard of care laboratory 
results will be used whenever possible.  All safety laboratory tests will be limited to local 
processing.  In addition, pediatric blood collection tubes will be used and capillary method of 
blood draw will be implemented whenever feasible.  PK samples will be collected from 
subjects unless deemed unsafe due to the risk from additional blood loss (per the 
Investigator’s judgment).
Table 4 shows the maximum volume of blood that will be drawn from each subject for the 
purposes of the study, apart from blood that is taken as part of subject’s normal standard of 
care.  The volume drawn for study purposes may be lower, as samples taken as standard of 
care will be used where possible.  The combined volume of all blood samples taken from a 
subject by the end of the study for investigational laboratory tests (ie, CBC with differential, 
chemistry panel, and PK analyses) is to be no more than 2.4cc/kg or 10cc total whichever is 
less.  Any deviation from this should be clinically justified.


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Table 4.
Volume of Blood to be Drawn from Each Subject
Assessment/Procedure
Study Visit
Total
Part A
Screening
Day 1
Day 2
Part B
Screening
Days 2-14
EOIV
CBC with differentiala
0.3 mL
0.3 mL
0.60 mL
Chemistry Panela
0.3 mL
0.3 mL
0.60 mL
PK Blood Sampleb
3 x 0.3 mL
0.90 mL
Total
0.6 mL
0.9 mL
0.6 mL
2.1 mL
Abbreviation: CBC=complete blood count; EOIV=End of IV.
a.
Not to be repeated if obtained on the same day per standard of care.
b.
Three PK samples (0.3 mL each) to be taken on Day 1 for Part A and during the period from Day 2 to 
Day 14 for Part B, according to the SCHEDULE OF ACTIVITIES.  For premature infants <1 kg only 
2 x 0.3 mL PK samples will be collected.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the Investigator are to be reported 
regardless of whether the event is determined by the Investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 


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previously forwarded reports.  In the rare situation that the Investigator does not become 
immediately aware of the occurrence of an event, the Investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the Investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the Investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
Investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The Investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject’s parent(s)/legal guardian/legally acceptable representative.  In 
addition, each study subject’s parent(s)/legal guardian/legally acceptable representative will 
be questioned about the occurrence of AEs in a non-leading manner.


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8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal [Early Termination] section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject’s parent(s)/legal guardian/legally 
acceptable representative provides informed consent, which is obtained before the subject’s 
participation in the study (ie, before undergoing any study-related procedure and/or receiving 
investigational product), through and including the Late Follow-Up (LFU) Visit (a minimum 
of 28 calendar days after the last administration of the investigational product).
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the Investigator becomes aware of them; at a minimum, all SAEs that the 
Investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the Investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the Investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the Investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the Investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The Investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the Investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
Investigator’s causality assessment is the determination of whether there exists a reasonable 


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possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
Investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the Sponsor.  If the Investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the Investigator determines that an SAE is associated with study procedures, 
the Investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;


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
Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the Investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);


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
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, the Investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the Investigator as described in previous sections, and will be handled as SAEs in 
the safety database.
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
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In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the Sponsor.
The subject should return to the Investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 


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anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the Liver Function Text (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of Investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
Not applicable.
8.4.3.2. Exposure During Breastfeeding
Not applicable.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the Investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the Investigator site file.


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8.4.4. Medication Errors and Lack of Efficacy
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors and lack of efficacy.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors and lack of 
efficacy*
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
*For lack of efficacy (particularly for studies conducted with vaccines, contraceptives, and products used in the 
treatment of life-threatening diseases or conditions [eg, anti-infectives]), see the Lack of Efficacy section below.
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the Sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4.4.2. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.


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9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be
maintained by the Sponsor and finalized before database lock.  The SAP may modify what is 
outlined in the protocol where appropriate; however, any major modifications of the primary 
endpoint definitions or their analyses will also be reflected in a protocol amendment.
Analysis sets are described below and in Figure 4.
Figure 4.
Study Analysis Sets
Abbreviations: CAZ-AVI = ceftazidime-avibactam; PK = pharmacokinetic.
9.1. Sample Size Determination
The primary objective of this study is to evaluate the pharmacokinetics, safety, and 
tolerability of CAZ-AVI in neonates and young infants with bacterial infections.  Limited 
efficacy information will be available as a secondary objective of Part B.  The study is not 
powered for inferential statistical analysis.  The sample size (48 subjects; 3 cohorts of 
16 subjects) is considered adequate to evaluate the pharmacokinetics of CAZ-AVI in 
neonates and infants and to provide critical insight into safety and toleration in this 
Intent-to-Treat (ITT)
All subjects
Safety
Received any amount of CAZ-AVI
Pharmacokinetic (PK)
Received a single IV dose of 
CAZ-AVI in Part A or at least 
3 consecutive doses of CAZ-AVI 
in Part B with at least 
1 ceftazidime and/or avibactam 
plasma PK measurement available
Modified Intent-to-Treat (MITT)
Received any amount of CAZ-AVI and
Meets minimal disease criteria of 
infection (inclusion criterion 4.1.3), 
excluding subjects with confirmed 
infection with a resistant pathogen known 
to be resistant to CAZ-AVI or confirmed 
Gram-positive, fungal, parasitic, or viral 
pathogen as the sole cause of the 
infection
Part B Only
Microbiological Intent-to-Treat 
(micro ITT)
Has at least 1 Gram-negative 
pathogen in an adequate 
initial/prestudy culture
Part B 
Only


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population.  Similarly, the sample size in Part B (24 subjects, 3 cohorts of 8 subjects) is 
considered adequate to provide insight into efficacy in this suspected or confirmed aerobic 
Gram-negative bacterial infection population.  Subjects who are not evaluable for PK 
(received a single IV dose of CAZ-AVI in Part A or at least 3 consecutive doses of 
CAZ-AVI in Part B with at least 1 ceftazidime and/or avibactam plasma measurement 
available) will be replaced.
9.2. Pharmacokinetic Analysis (Primary Objective Part A, Secondary Objective Part B)
The PK analysis set will consist of all subjects who received a single IV dose of CAZ-AVI in 
Part A or at least 3 consecutive doses of CAZ-AVI in Part B with at least 1 ceftazidime 
and/or avibactam plasma PK measurement available.  A listing of ceftazidime and avibactam 
plasma concentrations at the nominal sampling time by subject, cohort and Part will be 
provided.  For each Part, A and B and each Cohort 1, 2, and 3, the plasma concentration will 
be summarized by nominal sampling time using appropriate descriptive statistics 
(eg, number, mean, standard deviation (SD), minimum, median, maximum, geometric mean, 
and coefficient of variation). 
Individual plasma concentration profiles, using the PK analysis set for Cohorts 1 to 3, will be 
presented graphically using actual sample collection time on both linear and semilogarithmic 
scales, showing all subjects on a single plot for each cohort and analyte.  Median 
concentration-time profiles will be presented on both linear and semilogarithmic scales using 
nominal sampling time for both ceftazidime and avibactam.  Additional graphical 
presentations of PK data may be included at the discretion of the PK scientist.
In addition, the avibactam and ceftazidime concentration, pediatric subject demographics, 
and disease status data from Cohorts 1 to 3 will be combined with the data from appropriate 
previous clinical studies in pediatric subjects and/or adults for a population PK analysis.  The 
actual dosing and plasma sampling times will be used for the analysis.  A stand-alone 
population PK modelling and simulation analysis plan will be prepared and the results will be 
reported in a stand-alone report, for each Part A and Part B, outside of the clinical study 
report.
9.3. Safety Analysis (Primary Objective Part B, Secondary Objective Part A)
The safety analysis set will consist of all subjects who received any amount of IV study dose 
of CAZ-AVI.  Parts A and B will be summarized separately in addition to an overall safety 
summary.  No inferential statistical tests will be performed for any safety analyses.  For each 
safety parameter, the last assessment made before the first dose of study therapy will be used 
as the baseline for all analyses.  Summaries of demographics and other baseline 
characteristics will be provided.  The incidence of AEs, SAEs, deaths, and discontinuations 
due to AEs will be summarized by system organ class and preferred term according to the 
current version at time of study reporting of the Medical Dictionary for Regulatory Activities 
(MedDRA), by relationship to study therapy, and by severity.  All recorded AEs will be 
listed and tabulated by system organ class, preferred term and for each cohort.  Descriptive 
statistics of observed results and the change from baseline to selected postbaseline time 
points will be presented for clinical laboratory results and vital signs.  Tabulations and 


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listings of data for vital signs, weight, physical examinations, and clinical laboratory tests 
will be presented with abnormal or out-of-range values flagged.  Potentially clinically 
significant laboratory results will be summarized. 
9.4. Efficacy Analysis (Secondary Objective Part B)
The Intent-to-Treat (ITT) analysis set is defined as all subjects who have been enrolled in
each part of the study, regardless of whether or not treatment was received.
All cause mortality will be summarized with counts and proportions of deaths and 95% 
confidence intervals when applicable, for the ITT analysis set.
An assessment of clinical outcome will be made by the Investigator at EOIV, EOT, TOC and 
LFU.  Possible outcomes as defined in Table 5 are clinical cure, clinical improvement 
(oral/OPAT switch subjects only), clinical failure, or indeterminate.  A favorable clinical 
outcome is clinical cure or clinical improvement.  An outcome of clinical failure at EOIV 
will be carried forward to the subsequent visits.  Clinical outcomes will be summarized for 
the ITT, the Modified Intent-To-Treat (MITT) and the micro ITT Analysis Sets from Part B.  
The MITT Analysis Set will include all subjects who received any amount of CAZ-AVI and 
who met minimal disease criteria described in the inclusion criteria 4.1.3, defined as the 
presence of at least 1 clinical criterion and at least 1 laboratory criterion or 2 clinical criteria 
in the presence of, or as a result of suspected or proven bacterial infection requiring IV 
antibiotic therapy.  Subjects with confirmed infection with a pathogen known to be resistant 
to CAZ-AVI and subjects with a confirmed Gram-positive, fungal, parasitic, or viral 
pathogen as the sole cause of infection will be excluded from the MITT (a list of 
microorganisms that are considered pathogens will be provided in the SAP).  Proportions of 
subjects with a favorable efficacy response will be displayed overall and within each age 
cohort.  The number and percentage of subjects classified as clinical cure at EOIV, EOT, 
TOC, and LFU will be tabulated.
Microbiological responses will be summarized (also descriptively) only for the 
Microbiological ITT (micro ITT) Analysis Set from Part B including all subjects from the 
Part B ITT Analysis Set who have at least 1 Gram-negative pathogen in an adequate 
initial/prestudy culture. 


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9.4.1. Efficacy Response Definitions
Table 5.
Definition of Clinical Response Categories at the EOIV, EOT, TOC and 
LFU
Clinical 
Response
Definition
Clinical Cure
Resolution of all acute signs and symptoms of infection or 
improvement to such an extent that no further antibacterial therapy is 
required.
Clinical 
Improvementa
Subjects who switch to oral therapy and meet all of the following 
criteria at EOIV:

Afebrile (temperature 38.0C) for at least 24 hours.

Absence of new and improvement in at least 1 symptom or sign 
(ie, fever, pain, tenderness, elevated WBCs, elevated CRP) 
from Baseline and worsening of none.
Clinical Failureb
Subjects who received 48 hours of study treatment and meet any of 
the following: 

Discontinuation of study therapy due to insufficient therapeutic 
effect, including persistence, incomplete clinical resolution, 
worsening in signs and symptoms of infection, or isolation of a 
resistant pathogen that requires alternative nonstudy 
antibacterial therapy.

Discontinuation of study therapy due to a study therapy related 
AE and requirement for alternative nonstudy antibacterial 
therapy for infection.

Death in which infection is contributory.
Indeterminate
Study data are not available for evaluation of efficacy for any reason, 
including:

Death in which infection is clearly noncontributory.

Lost to follow up.

Extenuating circumstances precluding classification as a cure or 
failure.

Diagnosis of CNS infection, osteomyelitis, endocarditis, or 
NEC at any time after enrollment.

Received <48 hours of study therapy.
Abbreviations: AE=adverse event; CNS=central nervous system; NEC=necrotizing enterocolitis.
a.
Clinical improvement is only applicable at EOIV for subjects who are being switched to oral therapy after 
less than 14 days of IV CAZ-AVI. 
b.
A clinical failure at EOIV will be carried forward to EOT, TOC and LFU.


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9.4.2. Microbiological Response Definitions
The per-pathogen microbiological outcome categories at TOC are defined in Table 6.  
Favorable microbiological outcomes are eradication or presumed eradication.  
Baseline pathogens will be determined based on central laboratory data.  In the absence of 
any baseline central laboratory data, then local laboratory data will be used to identify 
baseline pathogens.  Rules for determination of pathogens will be described in the SAP.
Table 6.
Per-Pathogen Microbiological Outcomes Categories at TOC
Microbiological Responsea
Definition
Eradication
Source specimen demonstrated absence of the original 
baseline pathogen
Presumed eradication
Source specimen was not available to culture and the 
subject was assessed as a clinical cure
Persistence
Source specimen demonstrates continued presence of the 
original baseline pathogen
Presumed persistence
Source specimen was not available to culture and the 
subject was assessed as a clinical failure
Indeterminate
Source specimen was not available to culture and the 
subject’s clinical outcome was assessed as indeterminate
Abbreviations: TOC=Test of Cure
a.
For subjects who are clinical failures before TOC, the microbiological outcome will be carried forward to 
TOC and will be determined based on the cultures and/or clinical outcome at the time of the early clinical 
failure determination.
Per-subject microbiological response at TOC will be determined programmatically based on 
individual outcomes for each baseline pathogen, as per Table 7.
Table 7.
Per-Subject Microbiological Response
Number of 
pathogens at 
baseline
Pathogen 1 
Outcome at TOC
Pathogen 2
Outcome at TOC
Per-subject 
microbiological 
response at TOC
1 pathogen
Favorable
Favorable
Unfavorable
Unfavorable
Indeterminate
Indeterminate
2 pathogens
Favorable
Favorable
Favorable
Unfavorable
Unfavorable
Indeterminate
Indeterminate
Unfavorable
Any result
Unfavorable
Indeterminate
Favorable
Indeterminate
Unfavorable
Unfavorable
Indeterminate
Indeterminate


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Pathogens first appearing after Baseline (“emergent infections”) until the LFU are
categorized as in Table 8, using microbiological laboratory results. Counts and percentages 
of the number of subjects with a new infection and with a super infection will be presented.
Table 8.
Emergent Infections
Emergent Infections
Definition
Superinfection
A culture identified pathogen other than a baseline pathogen 
during the course of active treatment with study therapy requiring 
alternative antimicrobial therapy.
New infection
A culture identified pathogen other than a baseline pathogen at any 
time after study treatment has finished requiring alternative 
antimicrobial therapy. 
9.5. Interim Analysis
An interim report summarizing the existing data may be prepared for the purpose of 
Regulatory submission after the completion of Part A and completion of at least 4 subjects in 
each cohort of Part B.  Detailed methodology for the interim report will be included in the 
SAP.  As this is an open-label study, the Sponsor may also conduct unblinded reviews of the 
data during the course of the study for the purpose of safety assessment, facilitating dose 
adjustment decisions, facilitating pharmacokinetic (PK)/pharmacodynamic (PD) modeling, 
and/or to support clinical development.
9.6. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC).
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the charter.  The recommendations made by the E-DMC to alter the conduct of 
the study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
that are not endpoints, to regulatory authorities, as appropriate. 
9.7. Safety Review Committee
A Safety Review Committee (SRC) consisting of the study team physician, international 
coordinating Investigator or delegate, global safety/risk lead or delegate, therapeutic area 
director or delegate and the clinical pharmacologist/pharmacometrician or delegate will 
assess PK, safety and tolerability from each cohort.  With the exception of the international 
coordinating Investigator or delegate, all members of the SRC will be members of the 
Sponsor organization.  Other team members may be asked to join as needed.


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10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
Investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the Investigator site may be subject to 
review by the Institutional Review Board (IRB)/Ethics Committee (EC), and/or to quality 
assurance audits performed by Pfizer, or companies working with or on behalf of Pfizer, 
and/or to inspection by appropriate regulatory authorities.
The Investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the Investigator will cooperate with Pfizer 
or its agents to prepare the Investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The Investigator site and 
Investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The Investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the Investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The Investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and/or paper form and will 
be password protected or secured in a locked room to prevent access by unauthorized third 
parties.
The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the Investigator or by an authorized staff member to attest that the 


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data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the Investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
Investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the Investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer. The 
Investigator must ensure that the records continue to be stored securely for so long as they 
are retained.
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
Investigator, another institution, or an independent third party arranged by Pfizer.
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The Investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the Investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.


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The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the Investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data. Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
The Investigator site will maintain a confidential list of subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement and applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.


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The Investigator must ensure that each study subject’s parent(s), legal guardian, or legally 
acceptable representative is fully informed about the nature and objectives of the study, the 
sharing of data relating to the study and possible risks associated with participation, including 
the risks associated with the processing of the subject’s personal data.  The Investigator 
further must ensure that each study subject, or his or her legally acceptable representative, or 
parent(s) or legal guardian if a minor, is fully informed about his or her right to access and 
correct his or her personal data and to withdraw consent for the processing of his or her 
personal data.
The source documents must record how the Investigator determined that the person signing 
the consent was the subject’s legally acceptable representative and the consent signer’s 
relationship to the study subject (eg, parent).
The Investigator, or a person designated by the Investigator, will obtain written informed 
consent from the subject's parent(s), legal guardian, or legally acceptable representative
before any study-specific activity is performed.  The Investigator will retain the original of 
each subject's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the Investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the Investigator will inform Pfizer immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the Investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination, but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
The end of the trial in all other participating countries is defined as ‘the last visit of the last 
subject undergoing the study’ or the date of study closure in the case of early study 
termination, whichever date is later.


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The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  The 
Sponsor may also terminate the entire study prematurely if concerns for safety arise within 
this study or in any other study with CAZ-AVI.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
CAZ-AVI at any time.
If a study is prematurely terminated, Pfizer will promptly notify the Investigator.  After 
notification, the Investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.


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EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
Principal Investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the Investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The Investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the Investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The Investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the Investigator agrees that the first publication is 
to be a joint publication covering all Investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the Investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.


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Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
AVYCAZ. (ceftazidime-avibactam) [United States Package Insert]. Allergan USA, Inc., 
Irvine, CA 92612. 2019.
2.
Zavicefta. (ceftazidime-avibactam) [European Summary of Product Characteristics]. 
Pfizer Ireland Pharmaceuticals, Ringaskiddy, County Cork, Ireland. 2018.
3.
Engle WA. Age terminology during the perinatal period. Pediatrics. 
2004;114(5):1362-1364.
4.
Fortum (ceftazidime) [European Summary of Product Characteristics].  
GlaxoSmithKline, UK; June 2016.
5.
FORTAZ (ceftazidime for injection) [United States Package Insert].  GlaxoSmithKline, 
Research Triangle Park, NC.  January 2014.
6.
Miossec C, Claudon M, Levasseur P, Black MT.  The beta-lactamase inhibitor 
avibactam (NXL104) does not induce ampC beta-lactamase in Enterobacter cloacae.  
Infection & Drug Resistance.  2013;6:235-240.
7.
Anonymous. Ethical considerations for clinical trials on medicinal products conducted 
with minors: Recommendations of the expert group on clinical trials for the 
implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal 
products for human use. European Commission. 2017.
8.
Howie SR. Blood sample volumes in child health research: review of safe limits. Bull 
World Health Organ. 2011;89(1):46-53.


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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-24
Area under the plasma concentration-time curve from time zero 
to 24 hours
AVI
Avibactam
BE
Base excess
CAZ
Ceftazidime
CAZ-AVI
Ceftazidime-avibactam
CBC
Complete blood count
CGA
Corrected gestational age
cIAI
Complicated intra-abdominal infection
CK
Creatine kinase
Cmax
Maximum (or peak) plasma concentration
CNS
Central nervous system
CRF
Case Report Form
CRP
C-reactive protein
CSA
Clinical study agreement
CSF
Cerebrospinal fluid
cSSTI
Complicated skin and soft tissue infections
CT
Critical threshold concentration (AVI concentration high enough 
to provide protection to the CAZ component) 
CT
Clinical trial
CTA
Clinical trial application
CT scan
Computed tomography scan
cUTI
Complicated urinary tract infection
CXR
Chest x-ray
DILI
Drug-induced liver injury
EC
Ethics committee
E-DMC
External Data Monitoring Committee 
EDP
Exposure during pregnancy
eGFR
Estimated glomerular filtration rate
EOT
End of Treatment
EOIV
End of Intravenous
ESBL
Extended-spectrum β-lactamase
EU
European Union
EudraCT
European clinical trials database
GA
Gestational age
GCP
Good clinical practice


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Abbreviation
Term
GGT
Gamma-glutamyl transferase
HAP
Hospital-acquired pneumonia
HIV
Human immunodeficiency virus
IB
Investigator Brochure
ICH
International conference on harmonization
IND
Investigational new drug application
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
ITT
Intent-to-treat
IV
Intravenous
KPC
Klebsiella pneumoniae carbapenemase
LFT
Liver function test
LFU
Late follow-up
MDR
Multidrug resistant
MedDRA
Medical dictionary for regulatory activities
MIC
Minimum Inhibitory Concentration (lowest drug concentration 
that prevents visible microorganism growth)
MITT
Modified intent-to-treat
MRI
Magnetic resonance imaging
N/A
Not applicable
NEC
Necrotizing enterocolitis
NP
Nosocomial pneumonia
OAT
Organic anion transporter
OPAT
Outpatient parenteral antimicrobial therapy
PCD
Primary completion date
PCR
Polymerase chain reaction
pCO2
Carbon dioxide partial pressure
PD
Pharmacodynamic
pH
Negative logarithm of the hydrogen ion concentration (a 
measure of acidity or alkalinity)
PI
Principal investigator
PK
Pharmacokinetic
PMA 
Postmenstrual age
PT
Prothrombin time
PTA
Probability of Target Attainment (probably of achieving the 
specified drug exposure target)
q12h
Every 12 hours
q8h
Every 8 hours
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SmPC
Summary of Product Characteristics


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Abbreviation
Term
SOP
Standard Operating Procedure
SRC
Safety Review Committee
SRSD
Single reference safety document
spp.
Species
TBili
Total bilirubin
TOC
Test of Cure
ULN
Upper limit of normal
US
United States
USPI
United States Package Insert
VAP
Ventilator associated pneumonia


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Appendix 2. Calculation of Corrected Age for Pre-Term Infant Eligibility for Cohort 1
Pre-term infants are eligible for Cohort 1 if they have a corrected age >28 days to <3 months 
(<89 days).  The corrected age formula in Section 4.1.1 can be rearranged and expressed in 
days as follows:
Corrected age (in weeks) = chronological age in weeks – (40 – gestational age in weeks)
Corrected Age (days) = Chronological Age (days) + Gestational Age (days) – 280
Example 1:
Infant born at 26 weeks gestation (182 days)
Age since birth 19 weeks (133 days)
Corrected Age (days) = 133 + 182 – 280 = 35 days (eligible)
Example 2:
Infant born at 28 weeks 3 days gestation (199 days)
Age since birth 24 weeks 1 day (169 days)
Corrected Age (days) = 169 + 199 – 280 = 88 days (eligible)
Example 3:
Infant born at 35 weeks gestation (245 days)
Age since birth 17 week 5 days (124 days)
Corrected Age (days) = 124 + 245 – 280 = 89 days (ineligible)
An alternative terminology frequently used to describe infant age during the perinatal period 
is Postmenstrual Age (PMA), also known as Corrected Gestational Age (CGA).  The PMA or 
CGA is the gestational age plus the chronological age since birth.  PMA or CGA is usually 
described in number of weeks. A preterm infant born at a gestational age of 33 weeks who is 
currently 10 weeks old (chronological age) would have a PMA or CGA of 43 weeks.
Eligibility can be determined using PMA or CGA using the following formula.
Corrected Age (days) = PMA or CGA (days) – 280
Example 1:
Infant born at 26 weeks gestation (182 days)
Age since birth 19 weeks (133 days)
PMA or CGA (days) = 133 + 182 = 315 days (45 weeks)
Corrected Age (days) = 315 – 280 = 35 days (eligible)
Example 2:
Infant born at 28 weeks 3 days gestation (199 days)
Age since birth 24 weeks 1 day (169 days)
PMA or CGA (days) = 169 + 199 = 368 days (52 weeks 4 days)
Corrected Age (days) = 368 – 280 = 88 days (eligible)
Example 3:
Infant born at 35 weeks gestation (245 days)
Age since birth 17 week 5 days (124 days)
PMA or CGA (days) = 124 + 245 = 369 days (52 weeks 5 days)
Corrected Age (days) = 369 – 280 = 89 days (ineligible)


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Appendix 3. Table of Potential Alternative Doses of CAZ-AVI for Infants and Neonates
No alternative doses from this table are to be used except upon confirmation from the 
Sponsor in a written protocol Clarification Memorandum including the dosing rationale, any 
changes to the cohort enrollment sequence, and instructions for preparing and administering 
the alternative dose.  If the dosing interval for any cohort is increased from 8 hours to 
12 hours, then timing of the third PK sample will be changed to anytime between 
540 minutes (9 hours) and 600 minutes (10 hours) after stopping CAZ-AVI infusion.
Starting dose regimens for this protocol are underlined and bolded.
Dose (CAZ/AVI)
A
>28 days to <3 months
A1
25/6.25 mg/kg q8h
A2
30/7.5 mg/kg q8h
A3
35/8.75 mg/kg q8h
B
birth to 28 days (term)
B1
25/6.25 mg/kg q12h
B2
25/6.25 mg/kg q8h
B3
20/5 mg/kg q8h
B4
20/5 mg/kg q12h
B5
15/4.75 mg/kg q8h
C
birth to 28 days (preterm)
C1
25/6.25 mg/kg q12h
C2
20/5 mg/kg q8h
C3
20/5 mg/kg q12h
C4
15/4.75 mg/kg q8h
C5
15/4.75 mg/kg q12h

SAP_001.pdf: 
Protocol C3591024 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol C3591024
A PHASE 2A, 2-PART, OPEN-LABEL, NON-RANDOMIZED, MULTICENTER, 
SINGLE AND MULTIPLE DOSE TRIAL TO EVALUATE PHARMACOKINETICS,
SAFETY AND TOLERABILITY OF CEFTAZIDIME AND AVIBACTAM IN 
NEONATES AND INFANTS FROM BIRTH TO LESS THAN 3 MONTHS OF AGE 
WITH SUSPECTED OR CONFIRMED INFECTIONS DUE TO GRAM-NEGATIVE 
PATHOGENS REQUIRING INTRAVENOUS ANTIBIOTIC TREATMENT
Statistical Analysis Plan (SAP)
Version:
2.0
Date:
18-Sep-2019


Protocol C3591024 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................7
2.1. Study Objectives .......................................................................................................7
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoints (PK for Part A, Safety for Part B)............................................10
3.2. Secondary Endpoints (Safety for Part A, PK and efficacy for Part B) ...................10
3.3. Other Endpoints.......................................................................................................10
3.4. Baseline Variables...................................................................................................10
3.5. Safety Endpoints .....................................................................................................10
3.5.1. Adverse Events ...........................................................................................10
3.5.2. Laboratory Data..........................................................................................11
3.5.3. Vital Signs, Weight and Body Length........................................................11
4. ANALYSIS SETS ...............................................................................................................11
4.1. Full Analysis Set (Parts A and B) ...........................................................................12
4.2. Per Protocol Analysis Set........................................................................................12
4.3. Safety Analysis Set (Part A and Part B)..................................................................12
4.4. Efficacy Analysis Sets (Part B only).......................................................................13
4.5. Pharmacokinetic Analysis Set (Part A and part B) .................................................13
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................13
5.1. Hypotheses and Decision Rules ..............................................................................13
5.2. General Methods .....................................................................................................13
5.3. Methods to Manage Missing Data ..........................................................................14
6. ANALYSES AND SUMMARIES ......................................................................................14
6.1. Pharmacokinetic Analysis (Primary Objective Part A, Secondary Objective 
Part B)........................................................................................................................14
6.2. Efficacy Analysis (Secondary Objective Part B) ....................................................14
6.2.1. All-cause Mortality.....................................................................................14
6.2.2. Clinical Outcome........................................................................................15


Protocol C3591024 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 3
6.2.3. Microbiological Response ..........................................................................15
6.2.3.1. Per-pathogen Microbiological Response ..................................15
6.2.3.2. Per-subject Microbiological Response......................................16
6.2.3.3. Emergent Infections ..................................................................16
6.3. Other Endpoint(s)....................................................................................................17
6.4. Subset Analyses.......................................................................................................17
6.5. Baseline and Other Summaries and Analyses.........................................................17
6.6. Safety Summaries and Analyses .............................................................................17
6.6.1. Adverse Events ...........................................................................................17
6.6.2. Laboratory Data..........................................................................................18
6.6.3. Vital Signs, Weight and Body Length........................................................18
6.6.4. Study Treatment Exposure .........................................................................18
6.6.5. Prior and Concomitant Medications...........................................................18
7. INTERIM ANALYSES.......................................................................................................18
7.1. Introduction .............................................................................................................18
7.2. Interim Analyses and Summaries............................................................................18
7.3. Data Monitoring Committee ...................................................................................19
7.4. Safety Review Committee.......................................................................................19
8. APPENDICES .....................................................................................................................21
LIST OF TABLES
Table 1.
Summary of Changes..............................................................................................5
Table 2.
Definition of Age Cohorts ......................................................................................8
Table 3.
Per-Pathogen Microbiological Outcomes Categories at TOC..............................15
Table 4.
Per-subject Microbiological Response .................................................................16
Table 5.
Emergent Infections..............................................................................................17
Table 6.
Expected Age for Each Cohort.............................................................................25
LIST OF FIGURES
Figure 1.
Study Outline ..........................................................................................................9
Figure 2.
Study Analysis Sets ...............................................................................................12


Protocol C3591024 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 4
APPENDICES
Appendix 1. List of Microorganisms Considered to be Pathogens .........................................21
Appendix 2. Imputation of Incomplete Date of Birth and Derivation of Age.........................24


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Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 5
1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated Protocol 
Amendment
Rationale
Specific Changes
Version 1
27-Dec-2018
Original 
11-Jul-2018
N/A
N/A
Version 2
18-Sep-2019
Amendment 1
27-Jun-2019
Changes were 
made for 
consistency with 
wording used in 
protocol 
amendment 1
•
Table 2 in Section 2.2 has been revised to clarify that the upper limit of age described in 
inclusion criterion for Cohort 1 as <3 months corresponds to <89 days. Text for the definition 
of corrected age in the footnote of this table was expanded, and reference was made to 
Appendix 2 of the protocol. These revisions also apply to Table 6 of Appendix 2.
•
Analysis of the description of PK endpoints in Sections 3.1 and 3.2 were simplified.
•
It has been clarified in Section 4.4 that subjects in Part B only must meet at least 1 clinical and 
1 laboratory criterion or meet at least 2 of the clinical criteria to be included in the 
Modified ITT analysis set.  
•
It has been clarified in Section 4.5 that in Part A the PK analysis set requires subjects to have 
the single dose of CAZ-AVI (and not any amount) and in Part B, it requires subjects to have at 
least 3 consecutive doses of CAZAVI (and not 48 hours).
•
Text was updated in Sections 5.2 and 6.1 to use ‘nominal sampling time’ uniformly 
throughout the document in the description of the pharmacokinetic endpoint, for consistency 
with the description of PK endpoints in Section 2 of the protocol and in Section 3 of the SAP.
•
A paragraph was added to Section 6.2.3.1 to determine the use of central versus local lab 
results when determining baseline pathogens and their susceptibility.
•
In section 6.2.3.2. the definition of per-subject microbiological response in Table 4 has been 
revised to reflect the changes to Table 7 of the protocol. 
•
It has been clarified in section 6.6.2 how potentially clinically significant laboratory results 
will be summarized. 
•
Treatment exposure in Section 6.6.4 has been expanded to distinguish between the summaries 


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for Part A (in hours) and Part B (in calendar days, in addition to number of infusion).

Section 7.4 of the SAP has been revised to reflect change to Part B Cohort 3 enrollment 
sequence in the protocol as requested by the EMA Pediatric Committee (PDCO) on 19 Oct 
2018. Figure 3 was added to SAP to illustrate this change as per protocol amendment 1.
Review from 
microbiologist

Appendix 1. Added Kluyvera Intermedia and Providencia Stuartii to the list of pathogens.


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2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study C3591024.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
Note: in this document any text taken directly from the protocol is italicized.
2.1. Study Objectives
Part A Primary Objective:
To characterize the pharmacokinetics (PK) of a single intravenous dose of CAZ-AVI 
in hospitalized neonates and infants from birth to <3 months.
Part A Secondary Objective:
To evaluate the safety and tolerability of a single intravenous dose of CAZ-AVI in 
hospitalized neonates and infants from birth to <3 months.
Part B Primary Objective:
To evaluate the safety and tolerability of CAZ-AVI for the treatment of aerobic 
Gram-negative infection in neonates and infants from birth to <3 months.
Part B Secondary Objectives:
To evaluate the pharmacokinetic profile of multiple intravenous doses of CAZ-AVI 
in hospitalized neonates and infants from birth to <3 months.
To evaluate the efficacy of CAZ-AVI for the treatment of aerobic Gram-negative 
infection in neonates and infants from birth to <3 months.
2.2. Study Design
This is a 2-part Phase 2a non-randomized, multicenter, open-label, single and multi-dose PK 
study to assess PK, safety, and tolerability of CAZ-AVI in neonates and young infants aged 
birth to <3 months.  The efficacy of CAZ-AVI for the treatment of aerobic Gram-negative 
infection will be summarized descriptively as a secondary objective in the multi-dose portion 
of the trial.
This study is not randomized.  All enrolled subjects will receive CAZ-AVI either as a single 
dose in Part A or multiple doses in Part B. A total of 48 subjects are planned to be enrolled; 
24 in Part A and 24 in Part B. The study outline is provided in Figure 1.


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Parts A and B will each be divided into 3 age cohorts according to Table 2.
Table 2.
Definition of Age Cohorts
Cohort
Age
Part A
Part B
1
Term infants (GA 37 weeks) age >28 days to <3 months (<89 days) or 
pre-term infants with corrected age >28 days to <3 months (<89 days)
n=8
n=8
2
Term neonates (GA 37 weeks) from birth to 28 days
n=8
n=8
3
Pre-term neonates (GA 26 to <37 weeks) from birth to 28 days
n=8
n=8
GA = Gestational Age , the time elapsed between the first day of the last menstrual period and birth; 
Corrected age is the age of the infant from the expected date of delivery, calculated by subtracting the number 
of weeks born before 40 weeks of gestation from the chronological age.  Corrected age (weeks) = chronological 
age in weeks – (40 – gestational age in weeks).  See Appendix 2 of protocol for calculation of corrected age in 
days and alternative perinatal age terminologies.


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Figure 1.
Study Outline
Abbreviations: CAZ-AVI = ceftazidime-avibactam; EOIV = End of IV; EOT = End of Treatment; F/U = Follow-Up; hr(s) = hour(s); ICD = Informed Consent 
Document; IV = Intravenous; LFU = Late Follow-Up; OPAT = outpatient parenteral antimicrobial therapy; TOC = Test of Cure.
Oral or
OPAT
Day -1 to 1
ICD and 
screening the 
day of or day 
before 1st dose 
of CAZ-AVI
Day 1
1st Dose of 
CAZ-AVI
Day 2
24 hr F/U
Day 3
48 hr F/U
LFU
28-35 
days after 
last dose 
of 
CAZ-AVI
Days 2-14
CAZ-AVI
(min 48hr)
EOIV
EOIV 
and/or
EOT
TOC
Part A
Part B
Optional oral or OPAT 
switch after 48 hrs
IV Days 2-14
IV
Plus optional Gram-positive coverage 
and aminoglycoside as needed


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints (PK for Part A, Safety for Part B)
Part A: CAZ and AVI plasma concentration by nominal sampling time.
Part B: safety and tolerability endpoints including adverse events (AEs), serious adverse 
events (SAEs), deaths, discontinuations due to AEs and laboratory abnormalities.
3.2. Secondary Endpoints (Safety for Part A, PK and efficacy for Part B)
Part A: safety and tolerability endpoints including adverse events (AEs), serious adverse 
events (SAEs), deaths, discontinuations due to AEs and laboratory abnormalities.
Part B: CAZ and AVI plasma concentration by nominal sampling time.
Efficacy secondary outcome measures for Part B include:

All-cause mortality.

Clinical outcome at EOIV, EOT, TOC and LFU.

Cure defined as clinical improvement and no need for further antibacterial treatment, 
7 to 14 days after end of treatment.

Microbiological eradication 7 to 14 days after end of treatment.

Emergent infections.
3.3. Other Endpoints
Not applicable.
3.4. Baseline Variables
Baseline will be defined as the latest measurement taken prior to start of IV study drug, 
unless otherwise specified.  The baseline assessment for vital signs that have multiple 
measures within one visit such as systolic and diastolic blood pressure, pulse and respiratory 
rates and oxygen saturation will be the average of the measurements within that visit. If 
multiple measures of temperature are available within one visit, the highest value will be 
summarized.
3.5. Safety Endpoints
Clinical Data Interchange Standards Consortium (CDISC) and Pfizer Standards (CaPs) will 
be used for the analysis of standard safety data. 
3.5.1. Adverse Events
An adverse event is considered treatment emergent relative to treatment if:


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
The event occurs for the first time on or after the start of study treatment and was not 
seen prior to the start of treatment, or

The event was observed prior to the start of study treatment but increased in severity 
during treatment.
The start of study treatment is defined as the start time of the first infusion of IV study drug.
No lag time will be defined, ie, any adverse event that meets the requirements described 
above will be considered treatment emergent. 
3.5.2. Laboratory Data
Laboratory data include urine output, blood chemistry, hematology and urinalysis.
3.5.3. Vital Signs, Weight and Body Length
Vital signs measures include temperature (C), systolic and diastolic blood pressure (mmHg), 
pulse rate (beats/min) , respiratory rate (breaths/min) and oxygen saturation (%). Weight (kg) 
and body length (cm) will be summarized along with vital signs.
4. ANALYSIS SETS
Analysis sets are described in the sections below and in Figure 2.


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Figure 2.
Study Analysis Sets
Abbreviations: CAZ-AVI = ceftazidime-avibactam; PK = pharmacokinetic.
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per standard operating procedures.
4.1. Full Analysis Set (Parts A and B)
The full analysis sets for Part A and Part B are each defined as all subjects who have been 
enrolled in each part of the study, regardless of whether or not treatment was received. These
analysis sets will be referred to in the summary outputs as intent-to-treat (ITT).  
4.2. Per Protocol Analysis Set 
There will not be a Per Protocol Analysis Set for this study.
4.3. Safety Analysis Set (Part A and Part B)
The Safety Analysis Sets for Part A and Part B are each defined as those subjects who 
received any amount of the investigational drug (CAZ-AVI) in the respective part. The 
safety analysis set is the primary population for treatment administration/compliance and
safety. 
Intent-to-Treat (ITT)
All subjects
Safety
Received any amount of CAZ-AVI
Pharmacokinetic (PK)
Received a single IV dose of CAZ-
AVI in Part A or at least 3 
consecutive doses of CAZ-AVI in 
Part B with at least 1 ceftazidime 
and/or avibactam plasma PK 
measurement available
Modified Intent-to-Treat (MITT)
Received any amount of CAZ-AVI and
Meets minimal disease criteria of 
infection (inclusion criterion 4.1.3 of 
protocol), excluding subjects with 
confirmed infection with a resistant 
pathogen known to be resistant to 
CAZ-AVI or confirmed Gram-positive, 
fungal, parasitic, or viral pathogen as the 
sole cause of the infection
Part B Only
Microbiological Intent-to-Treat 
(micro-ITT)
Has at least 1 Gram-negative 
pathogen in an adequate 
initial/prestudy culture
Part B 
Only


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4.4. Efficacy Analysis Sets (Part B only)
For Part B only, two efficacy analysis sets are defined:
Modified Intent-to-Treat (MITT): Received any amount of CAZ-AVI and meets 
minimal disease criteria of infection described in protocol inclusion criterion 
4.1.3 (defined as the presence of at least 1 clinical criterion and 1 laboratory 
criterion or meet at least 2 clinical criteria in the presence of, or as a result of 
suspected or proven bacterial infection requiring IV antibiotic therapy). Subjects 
with confirmed infection with a pathogen known to be resistant to CAZ-AVI and 
subjects with a confirmed Gram-positive, fungal, parasitic, or viral pathogen as the 
sole cause of infection will be excluded.  A list of microorganisms that are considered 
pathogens is provided in Appendix 1.
Microbiological Intent-to-Treat (micro ITT): Has at least 1 Gram-negative 
pathogen in an adequate initial/prestudy culture.
4.5. Pharmacokinetic Analysis Set (Part A and part B)
The Pharmacokinetic (PK) analysis set for Part A is defined as subjects who received a single 
IV dose of CAZ-AVI in Part A. The PK analysis set for Part B is defined as subjects who 
received at least 3 consecutive doses of CAZ-AVI in Part B. In order for a subject to be part 
of the PK analysis sets he/she must have at least 1 ceftazidime and/or avibactam plasma PK 
measurement available. 
In case of partial IV dose of CAZ-AVI, patients may be included in the PK analysis set as 
long as they have at least one PK measurement and received a quantifiable dose of CAZ-AVI 
(based on the rate and the duration of the infusion).
5. GENERAL METHODOLOGY AND CONVENTIONS
The final analysis will be performed after dataset release.
5.1. Hypotheses and Decision Rules
The primary objective of this study is to evaluate the pharmacokinetics, safety, and 
tolerability of CAZ-AVI in neonates and young infants with bacterial infections.  Limited 
efficacy information will be available as a secondary objective of Part B.  The study is not 
powered for inferential statistical analysis.  
5.2. General Methods 
Descriptive methods will be used to summarize all data. In general summaries will be 
presented overall and by cohort separately for Part A and Part B, unless otherwise stated.
Descriptive methods for binary data will include counts and percentages, and 
95% confidence interval for proportions when applicable. 


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In general, descriptive statistics for continuous data will include mean, standard deviation, 
median, minimum and maximum observed values. For each Part, A and B and each 
Cohort 1, 2, and 3, the plasma concentration will be summarized by nominal sampling time 
using appropriate descriptive statistics (eg, number, mean, standard deviation (SD), 
minimum, median, maximum, geometric mean, and coefficient of variation).
5.3. Methods to Manage Missing Data
In general, missing values will not be imputed. Partial date handling will be done according 
to CaPs. Imputation of incomplete date of birth for the purposes of deriving age will follow 
the algorithm in Appendix 2.
6. ANALYSES AND SUMMARIES
6.1. Pharmacokinetic Analysis (Primary Objective Part A, Secondary Objective Part B)
The PK analysis set defined in Section 4.5 will be used for all PK analysis.
A listing of ceftazidime and avibactam plasma concentrations at the nominal sampling times
by subject, cohort and Part will be provided.  For each Part, A and B and each Cohort 1, 2, 
and 3, the plasma concentration will be summarized by nominal sampling time using 
appropriate descriptive statistics (eg, number, mean, standard deviation (SD), minimum, 
median, maximum, geometric mean, and coefficient of variation). 
Individual plasma concentration profiles will be presented graphically using actual sample 
collection time on both linear and semilogarithmic scales, showing all subjects on a single 
plot for each cohort and analyte.  Median concentration-time profiles will be presented on 
both linear and semilogarithmic scales using nominal sampling time for both ceftazidime and 
avibactam.  Additional graphical presentations of PK data may be included at the discretion 
of the PK scientist.
In addition, the avibactam and ceftazidime concentration, pediatric subject demographics, 
and disease status data from Cohorts 1 to 3 will be combined with the data from appropriate 
previous clinical studies in pediatric subjects and/or adults for a population PK analysis.  
The actual dosing and plasma sampling times will be used for the analysis.  A stand-alone 
population PK modelling and simulation analysis plan will be prepared and the results will 
be reported in a stand-alone report, for each Part A and Part B, outside of the clinical study 
report.
6.2. Efficacy Analysis (Secondary Objective Part B)
6.2.1. All-cause Mortality
All cause mortality will be summarized with counts and proportions of deaths and 
95% confidence intervals when applicable, for the ITT analysis set.


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6.2.2. Clinical Outcome
An assessment of clinical outcome will be made by the Investigator at EOIV, EOT, TOC and 
LFU. An outcome of clinical failure at EOIV will be carried forward to the subsequent visits.  
Possible outcomes are clinical cure, clinical improvement (oral/OPAT switch subjects only)), 
clinical failure, or indeterminate.  A favorable clinical outcome is clinical cure or clinical 
improvement.  
Clinical outcomes will be summarized descriptively for all efficacy analysis sets from Part B: 
ITT, MITT, and micro-ITT. For each nominal timepoint (EOIV, EOT, TOC, and LFU)
proportions of subjects with each clinical outcome, and with a favorable clinical outcome 
will be displayed overall and within each cohort.  
Counts and proportions of patients with a clinical outcome of cure 7 to 14 days after end of 
treatment (ie, at TOC) will be presented along with a 95% confidence interval.
6.2.3. Microbiological Response 
Summaries of microbiological responses will be presented only for the micro-ITT analysis 
set. 
6.2.3.1. Per-pathogen Microbiological Response
The per-pathogen microbiological outcome categories at TOC are defined in Table 3.  
Favorable microbiological outcomes are eradication or presumed eradication.
Table 3.
Per-Pathogen Microbiological Outcomes Categories at TOC
Microbiological Responsea
Definition
Eradication
Source specimen demonstrated absence of the original baseline 
pathogen
Presumed eradication
Source specimen was not available to culture and the subject 
was assessed as a clinical cure
Persistence
Source specimen demonstrates continued presence of the 
original baseline pathogen
Presumed persistence
Source specimen was not available to culture and the subject 
was assessed as a clinical failure
Indeterminate
Source specimen was not available to culture and the subject’s 
clinical outcome was assessed as indeterminate
Abbreviations: TOC=Test of Cure.
a.
For subjects who are clinical failures before TOC, the microbiological outcome will be carried forward to 
TOC and will be determined based on the cultures and/or clinical outcome at the time of the early clinical 
failure determination.
Baseline pathogen data will be determined based on central laboratory data.  In the absence 
of any baseline central laboratory data, then local laboratory data will be used to identify 
baseline pathogens and their susceptibility.  A list of microorganisms that are considered to 
be pathogens are described in Appendix 1.


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When available, results from the central laboratory for the multi-locus sequence typing 
(MLST) will be used to determine eradication or persistence on microorganisms of the same 
species isolated at baseline and post-baseline. Otherwise persistence/eradication will be 
determined based on the species.
Per-pathogen summaries: Counts and proportions of pathogens with each per pathogen 
microbiological response (eradication, presumed eradication, persistence, presumed 
persistence or indeterminate) at TOC will be summarized, and the proportion of pathogens 
with a favorable per-pathogen microbiological response (eradication or presumed 
eradication) will be presented along with a 95% confidence interval. 
Per-pathogen listings: Where applicable, the β-lactmases of Gram negative pathogens based 
on the MIC profile  from any baseline or post-baseline isolates will presented in a listing.  
6.2.3.2. Per-subject Microbiological Response
Per-subject microbiological response at TOC will be determined programmatically based on 
individual outcomes for each baseline pathogen, as per Table 4.  
Table 4.
Per-subject Microbiological Response
Number of 
pathogens 
at baseline
Pathogen 1 
Outcome at TOC
Pathogen 2 
Outocome at TOC
Per-Subject 
microbiological 
Response at TOC
1 pathogen
Favorable
Favorable
Unfavorable
Unfavorable
Indeterminate
Indeterminate
2 pathogens
Favorable
Favorable
Favorable
Unfavorable
Unfavorable
Indeterminate
Indeterminate
Unfavorable
Any result
Unfavorable
Indeterminate
Favorable
Indeterminate
Unfavorable
Unfavorable
Indeterminate
Indeterminate
Per-subject summaries: Counts and proportions of subjects with each a favorable 
microbiological response at TOC will be presented along with a 95% confidence interval.
6.2.3.3. Emergent Infections
Pathogens first appearing after Baseline (“emergent infections”) until the LFU are 
categorized as in Table 5, using microbiological laboratory results. Counts and percentages 
of the number of subjects with a new infection and with a super infection will be presented.


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Table 5.
Emergent Infections
Emergent Infections
Definition
Superinfection
A culture identified pathogen other than a baseline pathogen during the 
course of active treatment with study therapy requiring alternative 
antimicrobial therapy.
New infection
A culture identified pathogen other than a baseline pathogen at any time 
after study treatment has finished requiring alternative antimicrobial 
therapy. 
6.3. Other Endpoint(s)
Not applicable.
6.4. Subset Analyses 
No subset analyses will be done for this study.
6.5. Baseline and Other Summaries and Analyses
CaPs standards will be used for the analysis of standard safety data:

Demographics (age, gestational age, gender, race and ethnicity);

Baseline characteristics (primary diagnosis, breast feeding);

Medical history;

Physical exam;

Signs and symptoms.
Baseline pathogens will summarized by presenting the number and percentage of subjects 
with each pathogen.
6.6. Safety Summaries and Analyses
6.6.1. Adverse Events
Parts A and B will be summarized separately in addition to an overall safety summary
(ie, Part A and B patients in one single AE summary table).  No inferential statistical tests 
will be performed for any safety analyses.  The incidence of treatment emergent AEs, SAEs, 
deaths, and discontinuations due to AEs will be summarized by system organ class and 
preferred term according to the current version at time of study reporting of the Medical 
Dictionary for Regulatory Activities (MedDRA), by relationship to study therapy, and by 
severity.  All recorded AEs will be listed and tabulated by system organ class, preferred term 
and for each cohort.  
In addition to the above mentioned summaries of AEs, the incidence of treatment emergent 
AEs up to EOIV will also be summarized for patients in Part B.


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6.6.2. Laboratory Data
Descriptive statistics of observed results and the change from baseline to selected 
postbaseline time points (Days 2 and 3 for Part A; EOIV, EOT, TOC, LFU for Part B) will 
be presented for clinical laboratory results. Shift tables will summarize the number of 
patients who have a shift in categories of laboratory data from baseline to worst value up to 
end of IV treatment (Part B only) and from baseline to worst value anytime in study up to 
LFU.
Listings of data for clinical laboratory tests will be presented with abnormal or out-of-range 
values flagged for each patient. Potentially clinically significant laboratory results will be
summarized. Laboratory data will be medically assessed for potential clinically significance, 
and summarized in the clinical study report through listings.
6.6.3. Vital Signs, Weight and Body Length
Tabulations and listings of data for vital signs, weight, body length, and physical 
examinations tests will be presented.  
6.6.4. Study Treatment Exposure
For Part A treatment exposure will be summarized with descriptive statistics (mean, SD,
median, range) of the duration (in hours) of the single dose of CAZ-AVI
For Part B treatment exposure to CAZ-AVI will be summarized with descriptive statistics of
the number of calendar days subjects were exposed to CAZ-AVI, with counts and 
percentages of subjects who were exposed to each category of number of days of exposure
and also with descriptive statistics of the total number of IV infusions received by patients. 
Summaries will also be presented for the number of days subjects were exposed to 
oral/OPAT treatment for infection and also for the overall combined number of days subjects 
were exposed to CAZ-AVI and oral/OPAT treatment.  
6.6.5. Prior and Concomitant Medications
Prior and concomitant medications received by the subject and by the mother of subjects who 
are being breastfed will be summarized using standard summaries. Separate summaries will 
be presented for antibiotic medications and medications other than systemic antibiotics.
7. INTERIM ANALYSES
7.1. Introduction
This is an open-label, single arm study. All the interim analyses described in this section are 
for descriptive purposes.
7.2. Interim Analyses and Summaries
An interim report summarizing the existing data may be prepared for the purpose of 
Regulatory submission after the completion of Part A and completion of at least 4 subjects in 
each cohort of Part B.  Detailed methodology for the interim report will be included in an 
SAP amendment, as appropriate, prior to the conduct of any interim analysis.  


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As this is an open label study, the Sponsor may also conduct unblinded reviews of the data 
during the course of the study for the purpose of safety assessment, facilitating dose 
adjustment decisions, facilitating pharmacokinetic (PK)/pharmacodynamic (PD) modeling, 
and/or to support clinical development.
7.3. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC).
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the charter.  The recommendations made by the E-DMC to alter the conduct of 
the study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
that are not endpoints, to regulatory authorities, as appropriate.
7.4. Safety Review Committee
A Safety Review Committee (SRC) consisting of the study team physician, international 
coordinating Investigator or delegate, global safety/risk lead or delegate, therapeutic area 
director or delegate and the clinical pharmacologist/pharmacometrician or delegate will 
assess PK, safety and tolerability from each cohort.  With the exception of the international 
coordinating Investigator or delegate, all members of the SRC will be members of the 
Sponsor organization.  Other team members may be asked to join as needed.
The SRC will assess PK and safety data after the first 4 subjects are completed in Part A 
Cohort 1, before initiating simultaneous enrollment of remaining cohorts in Part A and 
Cohorts 1 and 2 in Part B.  SRC will also re-assess after the first 4 subjects are enrolled into 
each cohort of Parts A and B. The SRC will assess the PK, safety and toleration of CAZ-AVI 
after the first 4 subjects are completed in Part A Cohort 3, before initiating enrollment in 
Part B Cohort 3. The sequence of cohort startup is provided in Figure 3.


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Figure 3.
Cohort Start Up
Part A Cohort 1: >28 days to <3 months, n=8
Part A Cohort 2: Full Term to 28 days, n=8
Part B Cohort 1: >28 days to <3 months, n=8
Part B Cohort 2: Full Term to 28 days, n=8
Part A Cohort 3: Premature to 28 days, n=8
Part B Cohort 3: Premature to 28 days, n=8
*The SRC will assess the PK, safety and toleration of CAZ AVI after the first 4 subjects are completed in Part A 
Cohort 3, before initiating enrollment in Part B Cohort 3.
4
4
8
8
8
8
Initiate enrollment with 
Part A Cohort 1
Safety Review Committee (SRC) assesses PK 
and safety after first 4 subjects are completed 
in Part A Cohort 1, before initiating 
simultaneous enrollment of remaining cohorts 
in Part A and Cohorts 1 and 2 in Part B.  SRC 
will also re-assess after the first 4 subjects 
are enrolled into each cohort of Parts A and 
B. 
4*
4


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8. APPENDICES 
Appendix 1. List of Microorganisms Considered to be Pathogens
Name of microorganism
Pathogen Classification
Enterobacteriaceae
Name of microorganism
Pathogen Classification
Enterobacteriaceae
ACIDAMINOCOCCUS
No
Anaerobe
BACTEROIDES NORDII
No
Anaerobe
ACINETOBACTER
No
Gram-neg
BACTEROIDES OVATUS
No
Anaerobe
ACINETOBACTER ANITRATUS
No
Gram-neg
BACTEROIDES STERCORIS
No
Anaerobe
ACINETOBACTER CALCOACETICUS-
BAUMANNII COMPLEX
No
Gram-neg
BACTEROIDES THETAIOTAOMICRON
No
Anaerobe
ACINETOBACTER JOHNSONII
No
Gram-neg
BACTEROIDES UNIFORMIS
No
Anaerobe
ACINETOBACTER LWOFFII
No
Gram-neg
BACTEROIDES VULGATUS
No
Anaerobe
ACTINOMYCES
No
Anaerobe
BETA STREPTOCOCCUS, GROUP C
No
Gram-pos
ACTINOMYCES MEYERII
No
Anaerobe
BETA STREPTOCOCCUS, GROUP F
No
Gram-pos
ACTINOMYCES NAESLUNDII
No
Anaerobe
BETA STREPTOCOCCUS, GROUP G
No
Gram-pos
ACTINOMYCES ODONTOLYTICUS
No
Anaerobe
BIFIDOBACTERIUM
No
Anaerobe
ACTINOMYCES TURICENSIS
No
Anaerobe
BIFIDOBACTERIUM ADOLESCENTIS
No
Anaerobe
AEROBIC GRAM-POSITIVE BACILLUS
No
Gram-pos
BIFIDOBACTERIUM BIFIDUM
No
Anaerobe
AEROCOCCUS VIRIDANS
No
Gram-pos
BIFIDOBACTERIUM LONGUM
No
Anaerobe
AEROMONAS
No
Gram-neg
BIFIDOBACTERIUM PSEUDOCATENULATUM
No
Anaerobe
AEROMONAS HYDROPHILA
No
Gram-neg
BREVIBACTERIUM
No
Gram-pos
AEROMONAS HYDROPHILA COMPLEX
No
Gram-neg
BREVUNDIMONAS VESICULARIS
No
Gram-neg
AEROMONAS PUNCTATA
No
Gram-neg
BURKHOLDERIA
No
Gram-neg
AEROMONAS SOBRIA
No
Gram-neg
BURKHOLDERIA CEPACIA
No
Gram-neg
AEROMONAS VERONII
No
Gram-neg
BURKHOLDERIA CEPACIA COMPLEX
No
Gram-neg
ALCALIGENES
No
Gram-neg
CANDIDA
No
ANAEROBIC BACTERIA
No
Anaerobe
CANDIDA ALBICANS
No
ANAEROBIC COCCUS
No
Anaerobe
CANDIDA DUBLINIENSIS
No
ANAEROBIC GRAM-NEGATIVE BACILLUS
No
Anaerobe
CANDIDA GLABRATA
No
ANAEROBIC GRAM-NEGATIVE COCCUS
No
Anaerobe
CANDIDA KRUSEI
No
ANAEROBIC GRAM-POSITIVE BACILLUS
No
Anaerobe
CANDIDA PARAPSILOSIS
No
ANAEROBIC GRAM-POSITIVE COCCUS
No
Anaerobe
CANDIDA SPECIES NOT ALBICANS
No
ANAEROCOCCUS PREVOTII
No
Anaerobe
CANDIDA TROPICALIS
No
ANAEROCOCCUS TETRADIUS
No
Anaerobe
CAPNOCYTOPHAGA OCHRACEA
No
Gram-neg
ARCANOBACTERIUM HAEMOLYTICUM
No
Gram-pos
CHRYSEOBACTERIUM INDOLOGENES
No
Gram-neg
ARTHROBACTER
No
Gram-pos
CITROBACTER
Yes
Gram-neg
E
ARTHROBACTER CUMMINSII
No
Gram-pos
CITROBACTER AMALONATICUS
Yes
Gram-neg
E
ATOPOBIUM RIMAE
No
Anaerobe
CITROBACTER BRAAKII
Yes
Gram-neg
E
BACILLUS CEREUS
No
Gram-pos
CITROBACTER FREUNDII
Yes
Gram-neg
E
BACILLUS MEGATERIUM
No
Gram-pos
CITROBACTER FREUNDII COMPLEX
Yes
Gram-neg
E
BACILLUS SPECIES NOT ANTHRACIS
No
Gram-pos
CITROBACTER KOSERI
Yes
Gram-neg
E
BACTEROIDES
No
Anaerobe
CITROBACTER YOUNGAE
Yes
Gram-neg
E
BACTEROIDES CACCAE
No
Anaerobe
CLOSTRIDIUM
No
Anaerobe
BACTEROIDES CAPILLOSUS
No
Anaerobe
CLOSTRIDIUM ALDENENSE
No
Anaerobe
BACTEROIDES DOREI
No
Anaerobe
CLOSTRIDIUM BARATII
No
Anaerobe
BACTEROIDES FAECIS
No
Anaerobe
CLOSTRIDIUM BUTYRICUM
No
Anaerobe
BACTEROIDES FRAGILIS
No
Anaerobe
CLOSTRIDIUM CLOSTRIDIOFORME
No
Anaerobe
BACTEROIDES FRAGILIS GROUP
No
Anaerobe
CLOSTRIDIUM DIFFICILE
No
Anaerobe


Protocol C3591024 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 22
Name of microorganism
Pathogen Classification
Enterobacteriaceae
Name of microorganism
Pathogen
Classification
Enterobacteriaceae
CLOSTRIDIUM DISPORICUM
No
Anaerobe
FUSOBACTERIUM NAVIFORME
No
Anaerobe
CLOSTRIDIUM GLYCOLICUM
No
Anaerobe
FUSOBACTERIUM NECROPHORUM
No
Anaerobe
CLOSTRIDIUM HATHEWAYI
No
Anaerobe
FUSOBACTERIUM NUCLEATUM
No
Anaerobe
CLOSTRIDIUM HISTOLYTICUM
No
Anaerobe
FUSOBACTERIUM VARIUM
No
Anaerobe
CLOSTRIDIUM INNOCUUM
No
Anaerobe
GEMELLA HAEMOLYSANS
No
Gram-pos
CLOSTRIDIUM PERFRINGENS
No
Anaerobe
GEMELLA MORBILLORUM
No
Anaerobe
CLOSTRIDIUM RAMOSUM
No
Anaerobe
GLOBICATELLA SANGUINIS
No
Gram-pos
CLOSTRIDIUM SEPTICUM
No
Anaerobe
GRAM-NEGATIVE BACILLUS
No
Gram-neg
CLOSTRIDIUM SPOROGENES
No
Anaerobe
GRAM-POSITIVE BACILLUS
No
Gram-pos
CLOSTRIDIUM SYMBIOSUM
No
Anaerobe
GRAM-POSITIVE COCCUS
No
Gram-pos
CLOSTRIDIUM TERTIUM
No
Anaerobe
GRANULICATELLA ADIACENS
No
Gram-pos
COAGULASE NEGATIVE STAPHYLOCOCCUS No
Gram-pos
GRANULICATELLA ELEGANS
No
Gram-pos
COLLINSELLA AEROFACIENS
No
Anaerobe
GROUP D NON-ENTEROCOCCAL STREPTOCOCCUS No
Gram-pos
COMAMONAS KERSTERSII
No
Gram-neg
HAEMOPHILUS INFLUENZAE
No
Gram-neg
COMAMONAS TESTOSTERONI
No
Gram-neg
HAEMOPHILUS PARAINFLUENZAE
No
Gram-neg
CORYNEBACTERIUM
No
Gram-pos
HAFNIA ALVEI
Yes
Gram-neg
E
CORYNEBACTERIUM GLUCURONOLYTICUM No
Gram-pos
KLEBSIELLA
Yes
Gram-neg
E
CRONOBACTER SAKAZAKII
Yes
Gram-neg
E
KLEBSIELLA OXYTOCA
Yes
Gram-neg
E
DERMABACTER HOMINIS
No
Gram-pos
KLEBSIELLA OZAENAE
Yes
Gram-neg
E
DIALISTER PNEUMOSINTES
No
Anaerobe
KLEBSIELLA PNEUMONIAE
Yes
Gram-neg
E
DIPHTHEROIDS
No
Gram-pos
KLUYVERA
Yes
Gram-neg
E
EDWARDSIELLA HOSHINAE
Yes
Gram-neg
E
KLUYVERA ASCORBATA
Yes
Gram-neg
E
EGGERTHELLA
No
Anaerobe
LACTOBACILLUS
No
Anaerobe
EGGERTHELLA LENTA
No
Anaerobe
LACTOBACILLUS FERMENTUM
No
Anaerobe
EIKENELLA
No
Gram-neg
LACTOBACILLUS GASSERI
No
Anaerobe
EIKENELLA CORRODENS
No
Gram-neg
LACTOBACILLUS PARACASEI
No
Anaerobe
ENTEROBACTER
Yes
Gram-neg
E
LACTOCOCCUS GARVIEAE
No
Anaerobe
ENTEROBACTER AEROGENES
Yes
Gram-neg
E
LACTOCOCCUS LACTIS
No
Anaerobe
ENTEROBACTER ASBURIAE
Yes
Gram-neg
E
LEUCONOSTOC
No
Gram-pos
ENTEROBACTER CLOACAE
Yes
Gram-neg
E
LISTERIA
No
Gram-pos
ENTEROCOCCUS
No
Gram-pos
METHICILLIN RESIS. STAPHYLOCOCCUS AUREUS
No
Gram-pos
ENTEROCOCCUS AVIUM
No
Gram-pos
MICROCOCCUS LUTEUS
No
Gram-pos
ENTEROCOCCUS CASSELIFLAVUS
No
Gram-pos
MORGANELLA MORGANII
Yes
Gram-neg
E
ENTEROCOCCUS DURANS
No
Gram-pos
NEISSERIA CINEREA
No
Gram-neg
ENTEROCOCCUS FAECALIS
No
Gram-pos
NON-FERMENTATIVE GRAM-NEGATIVE BACILLUS No
Gram-neg
ENTEROCOCCUS FAECIUM
No
Gram-pos
PANTOEA
Yes
Gram-neg
E
ENTEROCOCCUS GALLINARUM
No
Gram-pos
PANTOEA AGGLOMERANS
Yes
Gram-neg
E
ENTEROCOCCUS HIRAE
No
Gram-pos
PARABACTEROIDES
No
Anaerobe
ENTEROCOCCUS RAFFINOSUS
No
Gram-pos
PARABACTEROIDES DISTASONIS
No
Anaerobe
ENTEROCOCCUS THAILANDICUS
No
Gram-pos
PARABACTEROIDES JOHNSONII
No
Anaerobe
ESCHERICHIA COLI
Yes
Gram-neg
E
PARABACTEROIDES MERDAE
No
Anaerobe
EUBACTERIUM
No
Anaerobe
PARVIMONAS MICRA
No
Anaerobe
EUBACTERIUM LIMOSUM
No
Anaerobe
PASTEURELLA MULTOCIDA
No
Gram-neg
FINEGOLDIA MAGNA
No
Anaerobe
PEPTONIPHILUS
No
Anaerobe
FLAVOBACTERIUM
No
Gram-neg
PEPTONIPHILUS ASACCHAROLYTICUS
No
Anaerobe
FUSOBACTERIUM
No
Anaerobe
PEPTONIPHILUS HAREI
No
Anaerobe
FUSOBACTERIUM MORTIFERUM
No
Anaerobe
PEPTOSTREPTOCOCCUS
No
Anaerobe


Protocol C3591024 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 23
Name of microorganism
Pathogen Classification Enterobacteriaceae
Name of microorganism
Pathogen Classification Enterobacteriaceae
PEPTOSTREPTOCOCCUS ANAEROBIUS
No
Anaerobe
STAPHYLOCOCCUS
No
Gram-pos
PEPTOSTREPTOCOCCUS STOMATIS
No
Anaerobe
STAPHYLOCOCCUS AUREUS
No
Gram-pos
PHOTOBACTERIUM DAMSELAE
No
Gram-neg
STAPHYLOCOCCUS CAPITIS
No
Gram-pos
PORPHYROMONAS
No
Anaerobe
STAPHYLOCOCCUS COHNII
No
Gram-pos
PORPHYROMONAS GINGIVALIS
No
Anaerobe
STAPHYLOCOCCUS EPIDERMIDIS
No
Gram-pos
PREVOTELLA
No
Anaerobe
STAPHYLOCOCCUS HAEMOLYTICUS
No
Gram-pos
PREVOTELLA BARONIAE
No
Anaerobe
STAPHYLOCOCCUS HOMINIS
No
Gram-pos
PREVOTELLA BIVIA
No
Anaerobe
STAPHYLOCOCCUS SAPROPHYTICUS
No
Gram-pos
PREVOTELLA BUCCAE
No
Anaerobe
STAPHYLOCOCCUS WARNERI
No
Gram-pos
PREVOTELLA BUCCALIS
No
Anaerobe
STENOTROPHOMONAS MALTOPHILIA
No
Gram-neg
PREVOTELLA DENTICOLA
No
Anaerobe
STREPTOCOCCUS
No
Gram-pos
PREVOTELLA HEPARINOLYTICA
No
Anaerobe
STREPTOCOCCUS ACIDOMINIMUS
No
Gram-pos
PREVOTELLA INTERMEDIA
No
Anaerobe
STREPTOCOCCUS AGALACTIAE
No
Gram-pos
PREVOTELLA LOESCHEII
No
Anaerobe
STREPTOCOCCUS ALPHA-HEMOLYTIC
No
Gram-pos
PREVOTELLA MELANINOGENICA
No
Anaerobe
STREPTOCOCCUS ANGINOSIS
No
Gram-pos
PREVOTELLA NIGRESCENS
No
Anaerobe
STREPTOCOCCUS ANGINOSUS GROUP
No
Gram-pos
PREVOTELLA ORALIS
No
Anaerobe
STREPTOCOCCUS ANGINOSUS-CONSTELLATUS
No
Gram-pos
PROPIONIBACTERIUM ACNES
No
Anaerobe
STREPTOCOCCUS BETA-HEMOLYTIC
No
Gram-pos
PROPIONIBACTERIUM PROPIONICUM
No
Anaerobe
STREPTOCOCCUS BOVIS
No
Gram-pos
PROTEUS
Yes
Gram-neg
E
STREPTOCOCCUS BOVIS GROUP
No
Gram-pos
PROTEUS MIRABILIS
Yes
Gram-neg
E
STREPTOCOCCUS CANIS
No
Gram-pos
PROTEUS RETTGERI
Yes
Gram-neg
E
STREPTOCOCCUS CONSTELLATUS
No
Gram-pos
PROTEUS VULGARIS
Yes
Gram-neg
E
STREPTOCOCCUS CRISTATUS
No
Gram-pos
PROTEUS VULGARIS GROUP
Yes
Gram-neg
E
STREPTOCOCCUS DYSGALACTIAE SUBSP. EQUISIMILIS
No
Gram-pos
PROVIDENCIA
Yes
Gram-neg
E
STREPTOCOCCUS EQUINUS
No
Gram-pos
PSEUDOMONAS
No
Gram-neg
STREPTOCOCCUS GALLOLYTICUS
No
Gram-pos
PSEUDOMONAS AERUGINOSA
Yes
Gram-neg
STREPTOCOCCUS GROUP C
No
Gram-pos
PSEUDOMONAS ALCALIGENES
No
Gram-neg
STREPTOCOCCUS INTERMEDIUS
No
Gram-pos
PSEUDOMONAS FLUORESCENS
No
Gram-neg
STREPTOCOCCUS MILLERI
No
Gram-pos
PSEUDOMONAS MENDOCINA
No
Gram-neg
STREPTOCOCCUS MITIS
No
Gram-pos
PSEUDOMONAS PUTIDA
No
Gram-neg
STREPTOCOCCUS MITIS GROUP
No
Gram-pos
PSEUDOMONAS STUTZERI
No
Gram-neg
STREPTOCOCCUS MUTANS
No
Gram-pos
RAOULTELLA ORNITHINOLYTICA
Yes
Gram-neg
E
STREPTOCOCCUS ORALIS
No
Gram-pos
RAOULTELLA PLANTICOLA
Yes
Gram-neg
E
STREPTOCOCCUS PARASANGUINIS
No
Gram-pos
ROTHIA DENTOCARIOSA
No
Gram-pos
STREPTOCOCCUS PNEUMONIAE
No
Gram-pos
RUMINOCOCCUS GNAVUS
No
Anaerobe
STREPTOCOCCUS PYOGENES
No
Gram-pos
SALMONELLA SEROTYPE ENTERITIDIS
Yes
Gram-neg
E
STREPTOCOCCUS SALIVARIUS
No
Gram-pos
SERRATIA MARCESCENS
Yes
Gram-neg
E
STREPTOCOCCUS SALIVARIUS GROUP
No
Gram-pos
SHEWANELLA ALGAE
No
Gram-neg
STREPTOCOCCUS SANGUINIS
No
Gram-pos
SHIGELLA DYSENTERIAE
Yes
Gram-neg
E
STREPTOCOCCUS VIRIDANS
No
Gram-pos
SLACKIA EXIGUA
No
Anaerobe
STREPTOCOCCUS VIRIDANS GROUP
No
Gram-pos
SOLOBACTERIUM MOOREI
No
Anaerobe
VEILLONELLA
No
Anaerobe
This list will be reviewed by microbiologist and finalized prior to database lock.


Protocol C3591024 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 24
Appendix 2. Imputation of Incomplete Date of Birth and Derivation of Age
Imputation of incomplete date of birth (DOB) will be done using the following data available from the case report form: month and 
year of birth from the incomplete DOB, date of informed consent, expected age in days for each cohort.
Step 1. Find a range of plausible DOBs based on the known month and year of birth from the incomplete DOB.
Step 2. Find a range of plausible DOBs based in the date of informed consent and the expected age in days for each cohort according 
to Table 6.
Step 3. Determine the range of possible DOBs based on the intersection of the two ranges in Steps 1 and 2a.
Step 4. Use the midpoint of the range of possible DOBs in Step 3 as the imputed DOB; derive age by subtracting the imputed DOB 
from the date of informed consent.
Notes: 
a.
If the ranges of plausible DOBs found in Steps 1 and 2 are not overlapping and the data for incomplete DOB and date of 
informed conset are confirmed by the site to be correct, this represents a protocol deviation on the age of patients. In this 
case, the range of possible DOBs in Step 3 will be determined based on the range from Step 1 and the date of informed 
consent, without taking the expected age of the cohorts into consideration.
For example, if a term infant from Cohort 1 has an incomplete DOB of Aug2018, and the date of informed consent of 
18Aug2018 the ranges of plausible values described in Steps 1 and 2 are Range 1: 01Aug2018 to 31Aug2018, and Range 
2: 18May2018 to 20Jul2018. Since these two ranges of plausible DOBs are not overlapping, the range of possible DOBs in 
Step 3 will be determined using the range from Step 1 (01 to 31Aug2018) and the date of informed consent (18Aug2018), 
ie, 01Aug2018 to 18Aug2018. In this case the imputed DOB is 09Aug2018, therefore the derived age is 9 days.


Protocol C3591024 (PF 06947386)
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 25
Table 6.
Expected Age for Each Cohort
Cohort
Definition
Expected age for Cohort
1
Term infants age >28 days to <89 days or
From 29 to 88 days
Pre-term infants with corrected age 
>28 days to <89 days
The expected ages will depend on the corrected age (CA), and the gestational age (GA), where 
CA = Age - (40 – GA) X 7,  which is equivalent to Age = CA + (40 - GA) X 7
For example, for pre-term neonates with GA=30 weeks the interval for CA of 29 to 88 days 
correspond to an interval for the chronological age of 99 to 158 days, which represent the 
expected ages of pre-term infants in Cohort 1.
2
Term neonates from birth to <= 28 days
From birth to 28 days
3
Pre-term neonates from birth to <= 28 days
From birth to 28 days
GA = Gestational Age, the time elapsed between the first day of the last menstrual period and birth; 
Corrected age is the age of the infant from the expected date of delivery, calculated by subtracting the number of weeks born before 40 weeks of gestation from 
the chronological age. Corrected age (weeks) = chronological age in weeks – (40 – gestational age in weeks).  See Appendix 2 of protocol for calculation of 
corrected age in days and alternative perinatal age terminologies.